The SERPINA1 NM_000295.5:c.1096G>A (NP_000286.3:p.(Glu366Lys)) missense variant has previously been reported in somatic cancers (COSMIC; COSV99054006, n = 3 times). Experimental evidence: A controlled transgenic-mouse study showed approximately tenfold lower serum AAT despite comparable or higher hepatic RNA, with Z-allele accumulation, liver injury, and neonatal runting. Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic 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.SERPINA1 encodes alpha-1 antitrypsin, a serine protease inhibitor made mainly in the liver that helps control enzymes such as elastase, trypsin, and thrombin. Changes in this gene are associated with chronic obstructive pulmonary disease, emphysema, and chronic liver disease. No established role in cancer is indicated.
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: p.Glu366Lys is the established pathogenic SERPINA1 Z substitution p.Glu342Lys, and SpliceAI max delta is 0.00.
Met: a controlled transgenic-mouse study showed approximately tenfold lower serum AAT despite comparable or higher hepatic RNA, with Z-allele accumulation, liver injury, and neonatal runting.
Met at supporting strength: REVEL 0.686 meets the generic PP3 supporting threshold of >=0.644 for this missense variant.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS1 strong plus PS3 and PP3 supporting satisfy the generic ACMG/AMP 2015 1 Strong + 2 Supporting rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 25,605 / 1,614,142 alleles. Recorded AF 0.0158629. Recorded homozygote count 263.
This variant is present in gnomAD v2.1 (AF= 0.0112329; MAF= 1.12329%, 3176/282742 alleles, homozygotes = 26) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0183495; MAF= 1.83495%, 2369/129104 alleles, homozygotes = 23); grpmax FAF= 0.0177524.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.686. Refer to the recorded PP3/BP4 rationale for interpretation.
46 Pathogenic · 1 risk factor · 1 pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV99054006, n = 3 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 · 8 not met · 12 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No usable proband, parental, family segregation, or affected-relative non-segregation evidence was identified for NM_000295.5:c.1096G>A; PS2, PM6, PP1, and BS4 are therefore not assessed rather than inferred from unrelated variant or gene-level literature.
No VCEP covers SERPINA1 in this case; generic ACMG/AMP rules govern.
PS4 could not be assessed because no affected-case prevalence or case-control counts were available, despite review of the PS4-indexed literature.
PP4 and BP5 could not be assessed because the supplied materials lack patient-specific phenotype/family-history information and an alternate molecular diagnosis, respectively.
PP5 and BP6 are not met because the exact variant has no qualifying ClinVar expert-panel classification.
The variant is missense, so PP3 and BP4 use the mutually exclusive REVEL path; SpliceAI is not used for either criterion.
REVEL 0.686 meets PP3 supporting (>=0.644) but does not meet BP4 supporting (<=0.29).
No population criterion is applied as benign or pathogenic evidence: BA1 and PM2 fail their generic frequency thresholds, BS1 is not established because the observed allele frequency is compatible with the reported ZZ disease prevalence, and BS2 is not applicable because early full penetrance is not established.
The adjudication uses gnomAD filtering allele frequencies rather than popmax point estimates; the relevant ancestry sample sizes exceed 2,000 observed alleles.
No criteria match.
NM_000295.5:c.1096G>A produces NP_000286.3:p.Glu366Lys, corresponding to the mature-protein SERPINA1 Z allele p.Glu342Lys. The Z allele is explicitly described as Glu342Lys in a serpinopathy review and in a transgenic mouse study, with reduced circulating alpha-1-antitrypsin, hepatocyte retention, liver injury, and disease. SpliceAI max delta is 0.00, supporting a protein-level rather than splice-mediated effect.
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.
PS3 is met at supporting strength. The variant is the SERPINA1 Z allele, mature-protein Glu342Lys corresponding to NP_000286.3:p.(Glu366Lys). In PMID:3264419, human SERPINA1 M- and Z-allele constructs were introduced into transgenic mice, with the normal M allele providing a biologically relevant comparator. The study evaluated hepatic RNA expression, serum alpha1-antitrypsin concentrations, and tissue pathology using RNA blotting, ELISA/immunoblotting, and histologic, dPAS, and anti-alpha1-antitrypsin staining. The Z allele produced approximately tenfold lower serum alpha1-antitrypsin despite comparable or higher hepatic RNA expression, hepatic and tissue protein accumulation, diastase-resistant PAS-positive cytoplasmic globules, liver injury, and neonatal runting in the high-expression lineage. These controlled in vivo findings directly support a damaging effect on SERPINA1 protein handling and function. The evidence is not escalated beyond supporting because the supplied record documents one transgenic animal study and does not establish validated, reproducible clinical-diagnostic-laboratory performance.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
The variant is a missense substitution, NM_000295.5:c.1096G>A (NP_000286.3:p.(Glu366Lys)); therefore PP3 is evaluated through the REVEL path only, and the SpliceAI result is not used. REVEL is 0.686, meeting the generic ClinGen SVI supporting threshold of >= 0.644 from the supplied REVEL calibration (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established for it.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
PM2 is not met. The variant is common in population databases rather than absent or extremely rare: gnomAD v4.1 reports AF 0.0158629 and grpmax FAF 0.0191827, while gnomAD v2.1 reports AF 0.0112329 and grpmax FAF 0.0177524. These frequencies are far above the generic PM2 supporting threshold of <=0.0001, and multiple homozygotes are observed in both datasets.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
Generic ACMG/AMP PP5 concerns a reputable recent pathogenic report when the underlying evidence is unavailable for independent evaluation, but under the required application rule it may trigger only for an exact-variant ClinVar expert-panel classification. ClinVar submission audit identifies no expert-panel submission, no usable expert-panel classification, and only a non-expert research submission; the literature packet also provides no independently verified exact-variant pathogenic report suitable for PP5.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. Generic BA1 requires an allele frequency of at least 0.05. The highest applicable gnomAD filtering frequency is grpmax FAF 0.0191827 in gnomAD v4.1, and gnomAD v2.1 reports grpmax FAF 0.0177524; both are below 0.05. The relevant ancestry groups have more than 2,000 observed alleles, so the FAF values are not small-isolate artifacts. The established SERPINA1 Z allele disease association also argues against using a lower-confidence high point estimate to invoke a stand-alone benign code.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met from the generic 1% default alone. The required filtering frequency is grpmax FAF 0.0191827, but BS1 asks whether the frequency is greater than expected for the disorder, not merely whether it exceeds 0.01. The reported prevalence of homozygous ZZ alpha-1 antitrypsin deficiency is approximately 1 in 2,000 to 3,500 births. Using q=0.0191827, q^2=0.00036798, or approximately 1 in 2,718, which lies within that prevalence range. The Z allele is also a documented SERPINA1 disease allele with disease risk dependent on genotype and clinical modifiers, so the generic default does not establish BS1.
Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS3 is not met. The reviewed variant-specific in vivo study evaluated the SERPINA1 Z allele and demonstrated reduced serum alpha1-antitrypsin, intracellular accumulation, and liver injury relative to the M-allele comparator; it did not show no damaging effect on protein function or splicing. No variant-specific validated assay demonstrating preserved protein function or normal splicing was supplied.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BP1 is not supported because the available SERPINA1 disease evidence does not show a gene for which primarily truncating variants are known to cause disease. Instead, the established SERPINA1 Z allele is a missense substitution, p.Glu342Lys mature numbering / p.Glu366Lys precursor numbering, with demonstrated protein misfolding, intracellular retention, reduced serum protein, and liver and lung disease. This directly contradicts the primarily truncating premise of BP1.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is a missense substitution, so BP4 is evaluated through the REVEL path only; SpliceAI cannot provide BP4 support for this missense variant. REVEL is 0.686, which is above the generic BP4 supporting upper threshold of <= 0.29 from the supplied REVEL calibration (Pejaver et al. 2022, PMID:36413997), so BP4 is not met. The BayesDel score is not used because no generic ACMG-strength calibration is established for BayesDel.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Generic ACMG/AMP BP6 concerns a reputable recent benign report when the underlying evidence is unavailable for independent evaluation, but under the required application rule it may trigger only for an exact-variant ClinVar expert-panel classification of benign or likely benign. ClinVar submission audit identifies no expert-panel submission and no benign or likely-benign expert-panel classification; the available ordinary submission is pathogenic and non-expert.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
PS2 cannot be assessed because the available case evidence does not document a proband with a compatible disease phenotype, absence of family history, confirmed maternity, or confirmed paternity for NM_000295.5:c.1096G>A. No source provides a de novo observation or parental testing result.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Generic ACMG/AMP PS4 requires a statistically significant increase of the variant in affected individuals versus controls, with RR or OR >5.0 and a confidence interval that excludes 1. The literature_pass.json packet has no ai_classified_papers, and the two papers indexed for PS4 were checked in paper_extracts.json: PMID:24121147 discusses the SERPINA1 Z allele generally without naming c.1096G>A/p.(E366K) or reporting affected/control counts, while PMID:7045697 has no usable scientific text and does not provide counts. gnomAD v4.1 reports population frequency 0.0158629 (25605/1614142 alleles), but no affected-cohort frequency is available, so an OR/RR and 95% CI cannot be calculated and PS4 cannot be assessed. The governing operator is exactly >5.0; the required comparison cannot be written as a substituted inequality because the case OR/RR is unavailable.
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.
The variant is missense, but the available evidence does not establish that residue 366 lies in a mutational hotspot or a critical, well-established functional domain without benign variation. Cancer Hotspots reports no statistically significant hotspot for SERPINA1 E366, COSMIC reports only three somatic occurrences of the variant, and no SERPINA1 VCEP domain table is present. The pathogenic Z-allele mechanism does not itself establish the PM1 location 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.
PM3 cannot be assessed because the available evidence does not establish that NM_000295.5:c.1096G>A is present in an affected proband in trans with a pathogenic allele. No parental or offspring testing, haplotype result, family genotype, or affected-proband compound-heterozygous observation is documented. The gnomAD observations are population frequencies, including homozygotes, and do not establish phase or the required clinical context; ClinVar's aggregate classification does not provide the needed allelic observation.
PM3: For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.
The available evidence does not identify a different missense substitution at SERPINA1 residue 366 that has been established as pathogenic. The cited papers describe the same p.Glu366Lys/p.Glu342Lys Z variant used for PS1, not an alternate missense change at that residue, and pm5_candidates.json contains zero same-residue candidates. A validated alternate pathogenic comparator is therefore unavailable.
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.
PM6 cannot be assessed because the available case evidence does not document an assumed de novo occurrence of NM_000295.5:c.1096G>A. There is no proband-level report, parental testing result, or statement that the variant was de novo without maternity and paternity confirmation.
Assumed de novo, but without confirmation of paternity and maternity.
PP1 cannot be assessed because the available case evidence provides no affected family members, variant genotypes in relatives, phenotype information for relatives, or meioses/segregation observations for NM_000295.5:c.1096G>A. The evidence therefore cannot establish co-segregation or a stronger level based on increasing segregation data.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The available evidence does not establish both PP2 requirements at the SERPINA1 gene level: a low rate of benign missense variation and missense variants as a common disease mechanism. The Z allele demonstrates that a SERPINA1 missense mechanism exists, but no validated gene-wide benign-missense-rate analysis or disease-allele spectrum is provided; the case variant itself is common in gnomAD v4.1 at AF 0.0158629 with 263 homozygotes.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Generic ACMG/AMP PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The available evidence describes SERPINA1-associated alpha-1 antitrypsin deficiency generally, but provides no case-specific phenotype or family history for this variant, so specificity cannot be judged.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS4 cannot be assessed because the available case evidence identifies no affected family members who were tested and found not to carry NM_000295.5:c.1096G>A. No non-segregation observation is documented, and the available material does not permit evaluation of phenocopies or multiple pathogenic variants in the family.
Lack of segregation in affected members of a family.
BP2 cannot be assessed because no affected-proband or family-level observation documents this variant in trans with a pathogenic variant in a fully penetrant dominant disorder, or in cis with a pathogenic variant under any inheritance pattern. No phase testing, haplotype result, parental genotype, or offspring genotype is available. ClinVar's aggregate classification and gnomAD population observations do not establish either required cis/trans relationship.
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.
Generic ACMG/AMP BP5 requires the variant to be found in a case with an alternate molecular basis for disease. The available case and literature materials do not document a case carrying this exact variant with a confirmed alternate molecular cause, so BP5 cannot be 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_000295.5:c.1096G>A in SERPINA1 is a missense substitution predicted to produce NP_000286.3:p.(Glu366Lys). 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 SERPINA1, 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_000295.5:c.1096G>A in SERPINA1 is a missense substitution predicted to produce NP_000286.3:p.(Glu366Lys). 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 SERPINA1, 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
BS2 is not applicable under the stated generic rule because its applicability requires full penetrance expected at an early age. gnomAD contains 263 homozygotes in v4.1 and 26 in v2.1, but these population-database counts do not document healthy adult status, age, phenotype, or penetrance for individual carriers. Alpha-1 antitrypsin deficiency includes adult lung disease and genotype- and exposure-dependent clinical risk, so the early-age full-penetrance condition is not satisfied.
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.
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000295.5:c.1096G>A in SERPINA1 is a missense substitution predicted to produce NP_000286.3:p.(Glu366Lys). 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 SERPINA1, 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_000295.5:c.1096G>A in SERPINA1 is a missense substitution predicted to produce NP_000286.3:p.(Glu366Lys). 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 SERPINA1, 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 SERPINA1, mapped onto the exon structure of NM_000295.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)22885 / 1,180,016 | 0.019248 hom |
| European (Finnish)1185 / 64,030 | 0.0199 hom |
| Remaining individuals757 / 62,508 | 0.0124 hom |
| Ashkenazi Jewish278 / 29,606 | 0.0094 |
| Amish7 / 910 | 0.00771 hom |
| Admixed American280 / 60,028 | 0.0047 |
| African/African American196 / 75,012 | 0.00261 hom |
| Middle Eastern5 / 6,062 | 0.00082 |
| South Asian12 / 91,086 | 0.00013 |
| European (non-Finnish)2369 / 129,104 | 0.01823 hom |
| European (Finnish)451 / 25,112 | 0.0183 hom |
| Remaining individuals71 / 7,220 | 0.0098 |
| Ashkenazi Jewish87 / 10,364 | 0.0084 |
| Admixed American134 / 35,410 | 0.0038 |
| African/African American62 / 24,966 | 0.0025 |
| South Asian2 / 30,616 | 6.5e-05 |
This variant is present in gnomAD v4.1 (AF= 0.0158629; MAF= 1.58629%, 25605/1614142 alleles, homozygotes = 263) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0193938; MAF= 1.93938%, 22885/1180016 alleles, homozygotes = 248); grpmax FAF= 0.0191827.
This variant is present in gnomAD v2.1 (AF= 0.0112329; MAF= 1.12329%, 3176/282742 alleles, homozygotes = 26) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0183495; MAF= 1.83495%, 2369/129104 alleles, homozygotes = 23); grpmax FAF= 0.0177524.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NM_000295.5:c.1096G>A (NP_000286.3:p.(Glu366Lys)); therefore PP3 is evaluated through the REVEL path only, and the SpliceAI result is not used. REVEL is 0.686, meeting the generic ClinGen SVI supporting threshold of >= 0.644 from the supplied REVEL calibration (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established for it.
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, so BP4 is evaluated through the REVEL path only; SpliceAI cannot provide BP4 support for this missense variant. REVEL is 0.686, which is above the generic BP4 supporting upper threshold of <= 0.29 from the supplied REVEL calibration (Pejaver et al. 2022, PMID:36413997), so BP4 is not met. The BayesDel score is not used because no generic ACMG-strength calibration is established for BayesDel.
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_000295.5:c.1096G>A in SERPINA1 is a missense substitution predicted to produce NP_000286.3:p.(Glu366Lys). 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 SERPINA1, 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 = 0.00). REVEL score = 0.686. BayesDel score = 0.191219.
10 paper records listed. 2 cited in the classification.
More than 100 allelic variants have been described with the most clinically relevant being the S (Glu264Val) and Z (Glu342Lys) alleles.37-40 The S allele is found in up to 28% of southern Europeans39 and reduces plasma levels of α1-antitrypsin to 60% of the normal M protein. The Z allele is present in 4% of northern Europeans39 and reduces the plasma level to 10–15% of normal. The decrease in plasma level is not associated with any clinical phenotype in the S homozygote but it has dramatic effects in those who are homozygous for the Z allele. The Z mutation causes the retention of α1-antitrypsin in hepatocytes as diastase resistant, periodic acid-Schiff (PAS) positive inclusions that cause both neonatal and adult liver disease.
Location Polymer Formation and Serpinopathies section, page 16; Figure 1 caption and adjacent discussion
Context Narrative review summarizing biochemical, biophysical, crystallographic, cellular, and clinical observations concerning alpha-1-antitrypsin variants; no new experiment involving this variant was performed in this paper.
The Z mutant contains a lysine instead of a glutamic acid at amino acid position 342 (2, 3).
Location Introduction/background; Results describing transgenic Z#1 and Z#2 mouse lineages
Context Human SERPINA1 M- and Z-allele genomic constructs were introduced into fertilized mouse embryos; hepatic RNA, serum alpha-1-antitrypsin, and tissue histopathology were evaluated by RNA blotting, ELISA/immunoblotting, histology, dPAS, and anti-alpha-1-antitrypsin staining.
The Z mutant of the AAT gene encodes the synthesis of a mutant protein, which is retained and accumulates in the liver rather than being appropriately secreted into serum. Accumulation of the Z mutant AAT protein in the liver can cause chronic liver disease, including cirrhosis and liver failure, in infants, children, and adults, whereas the decreased circulating levels of AAT significantly increase the risk of emphysematous lung disease in adults (4,5).
Background section, paragraph 2
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= 0.0158629; MAF= 1.58629%, 25605/1614142 alleles, homozygotes = 263) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0193938; MAF= 1.93938%, 22885/1180016 alleles, homozygotes = 248); grpmax FAF= 0.0191827.
This variant is present in gnomAD v2.1 (AF= 0.0112329; MAF= 1.12329%, 3176/282742 alleles, homozygotes = 26) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0183495; MAF= 1.83495%, 2369/129104 alleles, homozygotes = 23); grpmax FAF= 0.0177524.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (46 clinical laboratories) and as risk factor (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 17967)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.686. BayesDel score = 0.191219.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99054006, n = 3 times).
This variant does not lie in a statistically significant hotspot.