Variant classification summary

NM_025225.3:c.444C>G

PNPLA3 · NP_079501.2:p.(Ile148Met) · NM_025225.3

GRCh37: chr22:44324727 C>G · GRCh38: chr22:43928847 C>G

Gene: PNPLA3 Transcript: NM_025225.3

Final call

Benign

PS3 strong PS4 supporting BA1 stand-alone benign

Variant details

Gene

PNPLA3

Transcript

NM_025225.3

Protein

NP_079501.2:p.(Ile148Met)

gnomAD AF

0.23209785967766244 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: I148M knock-in mice developed a 2- to 3-fold hepatic-fat increase under a high-sucrose diet.

2

PS4 supporting: the exact variant had adjusted NAFLD OR 5.47 (95% CI 1.64-18.23).

3

BA1 stand-alone benign: gnomAD group-maximum FAF exceeded 0.05 in both v2.1 and v4.1.

Final determination: Generic ACMG/AMP 2015 fallback rules classify the variant as Benign because BA1 is met as a stand-alone benign criterion; the applied pathogenic criteria do not satisfy any pathogenic rule.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no previously established pathogenic PNPLA3 variant with the same p.Ile148Met amino-acid change but a different nucleotide change was documented.	clinvar
PS2	Not assessed	Not assessed: no documented proband-level de novo observation with confirmed maternity and paternity and no family history is available.
PS3	Met	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.	PMID:24917523 PMID:29158695 PMID:28073161
PS4	Met	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.	PMID:26200108 PMID:21381068 PMID:28073161
PM1	Not met	Not met: although p.Ile148Met is reported in the PNPLA3 active site, gnomAD v4.1 shows AF 0.232098 with 47,788 homozygotes, inconsistent with a region without benign variation.	PMID:29158695 gnomad_v4 clinvar cosmic hotspots
PM2	Not met	Not met: gnomAD v4.1 AF is 0.232098 with 47,788 homozygotes, far above the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no established recessive disorder, affected-proband allelic series, pathogenic partner, or parental testing demonstrates this variant in trans.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no different missense change at PNPLA3 residue 148 determined to be pathogenic was documented in the available evidence.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no affected-patient report describes this variant as assumed de novo without confirmed parental testing.
PP1	Not assessed	Not assessed: zero affected-family-member genotypes or informative meioses are reported for co-segregation analysis.
PP2	Not assessed	Not assessed: the evidence lacks a gene-wide demonstration of both low benign missense variation and a common missense disease mechanism for PNPLA3.
PP3	Not met	Not met: missense REVEL score 0.339 is below the PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no patient-specific phenotype or family history is documented to establish a highly specific single-gene disease presentation.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions for the exact variant and no expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Met	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.	gnomad_v2 gnomad_v4 clinvar
BS1	Not assessed	Not assessed: grpmax FAF is 0.502471, but no disorder-specific prevalence, penetrance, allelic heterogeneity, or maximum-credible-frequency calculation establishes that BS1 applies.	gnomad_v2 gnomad_v4 clinvar
BS2	Not assessed	Not assessed: gnomAD includes 47,788 v4.1 homozygotes, but healthy-adult status and full early-age penetrance are not established.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: the controlled knock-in study showed increased hepatic fat, not absence of a damaging effect, with a 2- to 3-fold increase on high-sucrose diet.	PMID:24917523 PMID:29158695 PMID:28073161
BS4	Not assessed	Not assessed: no tested affected family members are documented, so there is no non-segregation observation to evaluate.
BP1	Not assessed	Not assessed: no validated gene-level evidence shows that PNPLA3 disease is caused primarily by truncating rather than missense variants.
BP2	Not assessed	Not assessed: no phase-resolved pathogenic variant is documented in cis or trans, and no fully penetrant dominant PNPLA3 disorder is established.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.339 exceeds the BP4 supporting threshold of 0.29.	revel
BP5	Not assessed	Not assessed: no evidence documents an affected case carrying this variant with an independently established alternate molecular basis for disease.
BP6	Not met	Not met: the exact variant lacks a ClinVar expert-panel Benign or Likely benign classification, despite ordinary laboratory Benign submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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