The PNPLA3 NM_025225.3:c.444C>G (NP_079501.2:p.(Ile148Met)) missense variant has previously been reported in somatic cancers (COSMIC; COSV53377243, n = 19 times). Experimental evidence: Endogenous Pnpla3 I148M knock-in mice showed a 2- to 3-fold increase in hepatic fat on high-sucrose diet versus wild-type controls. Based on available guidelines, this variant is considered to be Benign.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.PNPLA3 encodes a membrane-associated enzyme involved in breaking down triacylglycerol, a major form of stored fat, in adipose cells and may help regulate the balance between energy storage and use. Changes in PNPLA3 are associated with susceptibility to fatty liver disease and related liver conditions. No established cancer role is described here.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at strong strength: endogenous Pnpla3 I148M knock-in mice showed a 2- to 3-fold increase in hepatic fat on high-sucrose diet versus wild-type controls.
Met at supporting strength: the exact variant had adjusted OR 5.47 (95% CI 1.64-18.23), exceeding the >5.0 threshold with a confidence interval excluding 1.
Met: gnomAD grpmax FAF is 0.5439 in v2.1 and 0.502471 in v4.1, both exceeding the 0.05 BA1 threshold with over 2,000 observed alleles.
Benign: BA1 stand-alone benign is met; PS3 strong plus PS4 supporting do not satisfy a pathogenic combination under generic ACMG/AMP rules.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 372,667 / 1,605,646 alleles. Recorded AF 0.232098. Recorded homozygote count 47788.
This variant is present in gnomAD v2.1 (AF= 0.271057; MAF= 27.10570%, 76540/282376 alleles, homozygotes = 12683) and has highest observed frequency in the Admixed American population (AF= 0.549302; MAF= 54.93017%, 19431/35374 alleles, homozygotes = 5584); grpmax FAF= 0.5439.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.339. Refer to the recorded PP3/BP4 rationale for interpretation.
2 Benign · 1 risk factor · 1 Likely risk allele · 1 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV53377243, n = 19 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 9 not met · 12 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For PNPLA3 p.Ile148Met, no qualifying same-amino-acid pathogenic alternate nucleotide change or pathogenic alternate missense change at residue 148 was documented. The active-site observation is outweighed for PM1 by abundant population variation and benign ClinVar submissions, while the gene-level prerequisites for PP2 and BP1 were not established.
None of PS2, PM6, PP1, or BS4 can be assessed because the available evidence contains no proband-parent de novo observation, affected-family-member segregation data, or non-segregation data.
PS4 is supported because PMID:26200108 reports an adjusted OR of 5.47 (95% CI 1.64-18.23), meeting the ACMG/AMP >5.0 and CI-not-including-1 rule; the meta-analysis result in PMID:21381068 is below threshold.
PP4 and BP5 cannot be assessed without patient-specific phenotype/family-history and alternate-molecular-basis information.
PP5 and BP6 are not met because ClinVar has no exact-variant expert-panel submission for this variant; ordinary laboratory assertions and aggregate labels are excluded.
This is a missense variant, so PP3 and BP4 were evaluated exclusively with REVEL under the generic ACMG/AMP computational path; the REVEL value of 0.339 meets neither criterion's applicable threshold.
No criteria match.
PS3 is met at strong strength. PMID:24917523 directly tested the PNPLA3 I148M substitution in an endogenous mouse knock-in model, using wild-type littermate controls and heterozygous and homozygous animals under chow and high-sucrose conditions. Homozygous I148M knock-in mice developed diet-dependent hepatic steatosis, with a 2- to 3-fold increase in liver fat on the high-sucrose diet, whereas no significant increase was observed on chow. The study also measured related phenotypes and found approximately 40-fold accumulation of PNPLA3 protein on hepatic lipid droplets despite similar mRNA levels. This is a directly variant-matched, controlled in vivo functional study with biological relevance to PNPLA3-associated hepatic disease and supports a damaging functional effect. The evidence is not from a validated clinical diagnostic laboratory, but the endogenous knock-in design, littermate controls, genotype dosage, dietary control, and concordant lipid-droplet findings support the default strong PS3 level rather than a weaker level.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PS4 is met at supporting strength. PMID:26200108 studied the exact PNPLA3 rs738409/c.444C>G (p.I148M) variant in Japanese participants and reported an adjusted odds ratio of 5.47 (95% CI 1.64-18.23) for NAFLD in the normal-weight longitudinal subgroup, comparing G/G with C/C; the CI excludes 1. This is a case-versus-unaffected comparison expressed as an odds ratio, and the paper already reported the OR, so no count-based OR calculation was needed. The independent meta-analysis in PMID:21381068 reported OR 3.488 (95% CI 1.859-6.545) for NASH, which does not reach the generic PS4 >5.0 threshold, while PMID:28073161 reported no clinical case-control or population-frequency data. The qualifying PMID:26200108 result therefore supplies the criterion evidence.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
BA1 is met on the required filtering allele frequency. The variant's gnomAD v2.1 grpmax FAF is 0.5439 and gnomAD v4.1 grpmax FAF is 0.502471, both far above the generic BA1 threshold of 0.05; the underlying highest-frequency population has more than 2,000 observed alleles in both datasets (v2.1 Admixed American 19,431/35,374; v4.1 Admixed American 30,366/59,864). The high frequency is not an isolate artifact. ClinVar shows conflicting classifications, including benign, risk factor, likely risk allele, and uncertain significance, with no expert-panel or pathogenic consensus; therefore the available record does not provide the pathogenic-consensus conflict that would block a stand-alone benign frequency call. This is a population-frequency adjudication only and does not negate the variant's reported low-penetrance/risk association with hepatic steatosis/NAFLD.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The variant is PNPLA3 p.Ile148Met (c.444C>G). The available ClinVar record and reviewed evidence identify this same nucleotide and amino-acid change, but do not document a previously established pathogenic PNPLA3 variant producing p.Ile148Met through a different nucleotide change. The PS1 requirement is therefore not met.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PNPLA3 p.Ile148Met is reported in a review as lying in the enzyme active site, and functional studies of I148M are available. However, generic PM1 also requires the hotspot or critical domain to be without benign variation. This variant itself is present at very high population frequency in gnomAD v4.1 (AF 0.232098; 372667/1605646 alleles; 47788 homozygotes), and ClinVar includes benign submissions. The supplied evidence therefore does not support a critical region without benign variation for applying PM1; the COSMIC observation and negative Cancer Hotspots result do not independently establish the generic PM1 requirement.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is not met because the variant is common in population controls, not absent or extremely rare. gnomAD v2.1 reports AF 0.271057 with 76,540/282,376 alleles and 12,683 homozygotes; gnomAD v4.1 reports AF 0.232098 with 372,667/1,605,646 alleles and 47,788 homozygotes. Both frequencies are far above the generic PM2 supporting threshold of <=0.0001.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The variant changes residue 148 from isoleucine to methionine. No different missense substitution at residue 148 that was determined to be pathogenic is documented in the supplied ClinVar evidence or comparator search artifact. The PM5 requirement is therefore not met.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
The variant is a missense substitution, NM_025225.3:c.444C>G (p.Ile148Met), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3 in this situation. REVEL is 0.339, below the generic PP3 supporting threshold of >=0.644, so PP3 is not met. The threshold is the ClinGen SVI REVEL calibration reported by Pejaver et al. 2022 (PMID:36413997).
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
PP5 is not met. ClinVar variation 341932 is an exact-variant record for PNPLA3 c.444C>G, but its review status is criteria provided, conflicting classifications and it has zero expert-panel submissions. The available Benign, risk factor, Likely risk allele, and uncertain submissions are ordinary laboratory assertions or aggregate record content, not an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification. Therefore the required PP5 trigger is absent.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BS3 is not met. The available variant-specific functional evidence does not show no damaging effect on PNPLA3 function or splicing. Instead, the controlled endogenous knock-in study in PMID:24917523 found diet-dependent hepatic steatosis in I148M mice, including a 2- to 3-fold increase in liver fat on a high-sucrose diet compared with controls, and approximately 40-fold accumulation of PNPLA3 protein on hepatic lipid droplets. Additional variant-specific cellular and biochemical findings summarized in PMID:29158695 and PMID:28073161 are also directionally consistent with altered PNPLA3 activity and hepatic or stellate-cell phenotypes. Therefore, the evidence is contrary to the BS3 definition rather than supportive of a benign functional effect.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense substitution, NM_025225.3:c.444C>G (p.Ile148Met), so the governing generic rule selects the REVEL path only; SpliceAI is not evidence for BP4 for a missense variant. REVEL is 0.339, which exceeds the generic BP4 supporting threshold of <=0.29, so BP4 is not met. The result is not a basis for substituting the SpliceAI score, and BayesDel is not used because no generic ACMG-strength calibration is established. The REVEL threshold is from the ClinGen SVI calibration reported by Pejaver et al. 2022 (PMID:36413997).
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP6 is not met. ClinVar variation 341932 is an exact-variant record, but it has zero expert-panel submissions and no exact-variant ClinVar expert-panel Benign or Likely benign classification. The available Benign assertions are ordinary laboratory submissions, and the record is conflicting; these cannot trigger BP6 under the required rule.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The available case evidence does not document a proband with a relevant Mendelian disease phenotype, absence of family history, or confirmed maternity and paternity for NM_025225.3:c.444C>G; therefore the de novo evidence required for PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PM3 cannot be assessed. The available case evidence identifies PNPLA3 c.444C>G (p.Ile148Met) as a common risk-associated variant, but does not establish a recessive Mendelian disorder for PNPLA3, an affected proband cohort, a second pathogenic variant, or parental/offspring testing demonstrating that this variant is in trans with a pathogenic variant. The available literature concerns population risk associations and functional studies, not phase or allelic observations.
For recessive disorders, detected in trans with a pathogenic variant... This requires testing of parents (or offspring) to determine phase.
The available case evidence does not report an assumed de novo occurrence of NM_025225.3:c.444C>G in an affected patient, with or without parental testing; therefore PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, informative meioses, co-segregation results, or family genotypes are reported for NM_025225.3:c.444C>G, and the available evidence does not establish a qualifying Mendelian family for this criterion; PP1 therefore cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The supplied evidence establishes that PNPLA3 p.Ile148Met is a common missense risk allele and has been functionally and clinically studied, but it does not establish the gene-level conditions required by PP2: a low rate of benign missense variation and missense variants as a common disease mechanism. No validated gene-wide missense constraint or disease-mechanism assessment satisfying both conditions was supplied.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The available evidence concerns population association and experimental or review-level descriptions of PNPLA3 I148M, not the phenotype or family history of the individual being interpreted. No patient-specific phenotype is supplied that can be judged highly specific for a disease with a single genetic etiology. The criterion therefore cannot be assessed from the available case information.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The frequency is well above the generic 1% BS1 default: grpmax FAF is 0.5439 in gnomAD v2.1 and 0.502471 in v4.1, with adequate allele counts. However, the available evidence characterizes PNPLA3 p.Ile148Met as a common low-penetrance risk allele for hepatic steatosis/NAFLD rather than a fully penetrant Mendelian disorder, and no disorder-specific prevalence, penetrance, allelic heterogeneity, or maximum-credible-allele-frequency calculation is supplied. Because the generic BS1 definition requires that the frequency be greater than expected for the disorder, the default 1% threshold alone is insufficient here; BS1 is not assessed rather than applied solely from frequency.
Allele frequency is greater than expected for the disorder.
gnomAD reports many homozygotes for the variant, including 12,683 in v2.1 and 47,788 in v4.1. These aggregate population counts do not establish that the individuals were healthy adults, and the available PNPLA3 evidence describes a common, incompletely penetrant, later-onset risk association with hepatic steatosis/NAFLD rather than a disorder expected to show full penetrance at an early age. Therefore the BS2 requirement is not demonstrated by homozygote counts alone.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
The available case evidence does not identify affected family members who were tested for NM_025225.3:c.444C>G and does not provide any non-segregation observations; therefore lack of segregation cannot be assessed as BS4.
Lack of segregation in affected members of a family.
The supplied evidence does not establish that PNPLA3-related disease is caused primarily by truncating variants. The reviewed literature focuses on the common p.Ile148Met missense risk allele and does not provide a validated gene-level comparison demonstrating a primarily truncating disease mechanism. BP1 therefore cannot be assessed from the available evidence.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed. The available evidence does not document a fully penetrant dominant PNPLA3 disorder, an affected proband carrying PNPLA3 c.444C>G in trans with a pathogenic variant, or any pathogenic variant in cis with this variant. No family testing or phase-resolved allelic observations are available. The cited PNPLA3 literature reports risk associations and functional studies rather than the cis/trans pathogenic-variant observations required for BP2.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
No case report or clinical record in the available evidence documents that this variant was found in a case with an alternate molecular basis for disease. Population association, functional studies, and conflicting laboratory classifications do not establish the BP5 circumstance. The criterion is therefore not assessed.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_025225.3:c.444C>G in PNPLA3 is a missense substitution predicted to produce NP_079501.2:p.(Ile148Met). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for PNPLA3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_025225.3:c.444C>G in PNPLA3 is a missense substitution predicted to produce NP_079501.2:p.(Ile148Met). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for PNPLA3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_025225.3:c.444C>G in PNPLA3 is a missense substitution predicted to produce NP_079501.2:p.(Ile148Met). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for PNPLA3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_025225.3:c.444C>G in PNPLA3 is a missense substitution predicted to produce NP_079501.2:p.(Ile148Met). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for PNPLA3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in PNPLA3, mapped onto the exon structure of NM_025225.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Admixed American30366 / 59,864 | 0.518187 hom |
| East Asian18554 / 44,770 | 0.413883 hom |
| Amish247 / 908 | 0.2729 hom |
| Middle Eastern1621 / 6,036 | 0.27223 hom |
| Remaining individuals14334 / 62,192 | 0.231679 hom |
| European (Finnish)14419 / 63,792 | 0.231683 hom |
| South Asian20382 / 90,806 | 0.222438 hom |
| European (non-Finnish)256142 / 1,172,928 | 0.2228251 hom |
| Ashkenazi Jewish6416 / 29,542 | 0.22727 hom |
| African/African American10186 / 74,808 | 0.14688 hom |
| Admixed American19431 / 35,374 | 0.555584 hom |
| East Asian7598 / 19,910 | 0.381498 hom |
| Remaining individuals1965 / 7,206 | 0.27279 hom |
| European (non-Finnish)29412 / 128,970 | 0.233393 hom |
| European (Finnish)5666 / 25,050 | 0.23650 hom |
| South Asian6768 / 30,572 | 0.22755 hom |
| Ashkenazi Jewish2271 / 10,356 | 0.22278 hom |
| African/African American3429 / 24,938 | 0.14246 hom |
This variant is present in gnomAD v4.1 (AF= 0.232098; MAF= 23.20979%, 372667/1605646 alleles, homozygotes = 47788) and has highest observed frequency in the Admixed American population (AF= 0.50725; MAF= 50.72498%, 30366/59864 alleles, homozygotes = 8187); grpmax FAF= 0.502471.
This variant is present in gnomAD v2.1 (AF= 0.271057; MAF= 27.10570%, 76540/282376 alleles, homozygotes = 12683) and has highest observed frequency in the Admixed American population (AF= 0.549302; MAF= 54.93017%, 19431/35374 alleles, homozygotes = 5584); grpmax FAF= 0.5439.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NM_025225.3:c.444C>G (p.Ile148Met), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3 in this situation. REVEL is 0.339, below the generic PP3 supporting threshold of >=0.644, so PP3 is not met. The threshold is the ClinGen SVI REVEL calibration reported by Pejaver et al. 2022 (PMID:36413997).
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is a missense substitution, NM_025225.3:c.444C>G (p.Ile148Met), so the governing generic rule selects the REVEL path only; SpliceAI is not evidence for BP4 for a missense variant. REVEL is 0.339, which exceeds the generic BP4 supporting threshold of <=0.29, so BP4 is not met. The result is not a basis for substituting the SpliceAI score, and BayesDel is not used because no generic ACMG-strength calibration is established. The REVEL threshold is from the ClinGen SVI calibration reported by Pejaver et al. 2022 (PMID:36413997).
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_025225.3:c.444C>G in PNPLA3 is a missense substitution predicted to produce NP_079501.2:p.(Ile148Met). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for PNPLA3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.339. BayesDel score = -0.326399.
8 paper records listed. 5 cited in the classification.
Nonalcoholic steatohepatitis (NASH) was more frequently observed in GG than CC homozygous (odds ratio [OR] 3.488, 95% confidence interval [CI] 1.859-6.545, random model; P < 2 3 1024; data from 2,124 patients).
Location Abstract; Results sections ‘Fatty Liver Disease and Liver Fat Content,’ ‘Histological Severity of NAFLD,’ and ‘ALT Levels’
Context Systematic review and meta-analysis of 16 association studies evaluating PNPLA3 rs738409 C/G genotypes across populations; pooled NASH analysis included 2,124 patients.
The major finding of this study is that Pnpla3148M/M KI mice develop diet-dependent hepatic steatosis. The I148M substitution did not lead to increased hepatic TG levels in chow-fed mice, but elicited a 2 to 3-fold elevation in liver fat content in sucrose-fed animals (Fig. 2).
Location Results, "Pnpla3 148M and Pnpla3 47A KI Mice Develop Hepatic Steatosis on a High-Sucrose Diet"; Discussion, first paragraph
Context Endogenous Pnpla3 I148M knock-in mice, including heterozygous and homozygous animals, compared with wild-type littermates under chow, high-sucrose, and high-fat dietary conditions; hepatic triglycerides, lipid-droplet morphology, liver enzymes, gene expression, glucose homeostasis, and lipid-droplet proteins were measured.
The PNPLA3 rs738409 polymorphism (encoding I148M) in the patatin-like phospholipase 3 (PNPLA3) gene has been consistently recognized to be a major genetic factor for the development of NAFLD and advanced liver diseases
Location Introduction, paragraph 2; Results, Tables 2 and 3
Context Cross-sectional and retrospective longitudinal observational analyses of Japanese health-screening participants: 740 participants cross-sectionally and 393 longitudinally with approximately 5.5 years of follow-up; genotyping used a real-time TaqMan allelic discrimination assay.
Primary human I148M HSCs displayed significantly higher expression and release of pro-inflammatory cytokines, such as CCL5 (p<0.01) and GM-CSF (p<0.001), thus contributing to migration of immune cells (p<0.05).
Location Abstract; Results, "The I148M PNPLA3 confers a pro-inflammatory phenotype to primary human HSCs" and subsequent I148M functional-assay sections
Context In vitro study using primary human hepatic stellate cells from homozygous WT C/C or I148M G/G donors, n=3 per group, plus LX-2 cells stably overexpressing PNPLA3 WT or I148M; assays included cytokine profiling, migration, proliferation, lipid droplets, retinol, reporter assays, JNK, AP-1, and fatty-acid profiling.
The PNPLA3 variant is a single-base polymorphism, which leads to the switch from a cytosine (C) to a guanine (G), resulting in an amino acid substitution of an isoleucine (I) to a methionine (M) at the position 148 (I148M) of the coding sequence.
Location Section: Hepatic functions of PNPLA3 genetic variant reported in vitro and in vivo
Context Review of recombinant human PNPLA3 assays, cultured hepatocytes, human hepatocytes, transgenic and knock-in mouse models, and human cohort studies.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.232098; MAF= 23.20979%, 372667/1605646 alleles, homozygotes = 47788) and has highest observed frequency in the Admixed American population (AF= 0.50725; MAF= 50.72498%, 30366/59864 alleles, homozygotes = 8187); grpmax FAF= 0.502471.
This variant is present in gnomAD v2.1 (AF= 0.271057; MAF= 27.10570%, 76540/282376 alleles, homozygotes = 12683) and has highest observed frequency in the Admixed American population (AF= 0.549302; MAF= 54.93017%, 19431/35374 alleles, homozygotes = 5584); grpmax FAF= 0.5439.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as risk factor (1 clinical laboratory) and as Likely risk allele (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 341932)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.339. BayesDel score = -0.326399.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53377243, n = 19 times).
This variant does not lie in a statistically significant hotspot.