Variant classification summary

NM_001127701.1:c.863A>T

SERPINA1 · NP_001121173.1:p.(Glu288Val) · NM_001127701.1

GRCh37: chr14:94847262 T>A · GRCh38: chr14:94380925 T>A

Gene: SERPINA1 Transcript: NM_001127701.1

Final call

Benign

PS1 strong PP3 supporting BA1 stand-alone benign

Variant details

Gene

SERPINA1

Transcript

NM_001127701.1

Protein

NP_001121173.1:p.(Glu288Val)

gnomAD AF

0.036359592660555 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: PS1 strong identifies the same pathogenic PiS amino-acid substitution.

2

Benign: PP3 supporting is met by REVEL 0.692 above the 0.644 threshold.

3

Benign: BA1 is met by the Amish allele frequency of 12.61%, above 5%.

Final determination: Under the generic ACMG/AMP 2015 fallback, BA1 alone establishes Benign; the pathogenic-direction PS1 strong plus PP3 supporting combination does not satisfy a 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	Met	Met: the established SERPINA1 PiS allele is the same Glu-to-Val substitution, reported as mature-protein Glu264Val versus precursor Glu288Val here.	PMID:29232161
PS2	Not assessed	Not assessed: No parental testing or de novo observation is documented, so confirmed maternity and paternity cannot be evaluated.
PS3	Not assessed	Not assessed: no available paper reports a validated functional assay of SERPINA1 c.863A>T (p.Glu288Val).	PMID:29232161 PMID:26141072 PMID:6602622
PS4	Not assessed	Not assessed: no variant-specific affected-versus-control counts, odds ratio, relative risk, or confidence interval are available to evaluate PS4.	PMID:26141072 PMID:6602622 gnomad_v4
PM1	Not assessed	Not assessed: no approved SERPINA1 domain or hotspot evidence establishes that residue 288 lies in a critical region without benign variation.	hotspots
PM2	Not met	Not met: non-cancer gnomAD frequencies are 2.27% in v2.1 exomes and 2.86% in v3.1 genomes, far above the PM2 <=0.01% threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: No affected-proband observation or parental/offspring testing demonstrates this variant in trans with a pathogenic variant.
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 assessed	Not assessed: no different pathogenic missense substitution at residue 288 is documented, while the known PiS change is the same substitution and belongs under PS1.	pm5_candidates
PM6	Not assessed	Not assessed: No assumed de novo occurrence or parental genotype data are documented for this proband.
PP1	Not assessed	Not assessed: No affected relatives or variant-specific co-segregation observations are documented for informative family meioses.
PP2	Not assessed	Not assessed: the available evidence lacks gene-wide measures for benign missense rate and the required common missense disease mechanism.
PP3	Met	Met at supporting strength: REVEL 0.692 exceeds the generic PP3 supporting threshold of 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient-specific phenotype or family history is available to determine whether the presentation is highly disease-specific.	PMID:26141072 PMID:6602622
PP5	Not met	Not met: ClinVar shows laboratory and aggregate Pathogenic assertions but no exact-variant expert-panel classification qualifying for PP5.	clinvar
BA1	Met	Met: Amish gnomAD v4.1 frequency is 12.61% (115/912 alleles), exceeding the generic BA1 >=5% threshold despite lower all-comers frequency.	gnomad_v4
BS1	Not assessed	Not assessed: frequency reaches 12.61% in Amish individuals, but prevalence, penetrance, and allelic-heterogeneity inputs for a maximum-credible-frequency calculation are unavailable.	gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: gnomAD shows 1,342 homozygotes, but BS2 requires healthy adults with full early-age penetrance, which does not fit this reduced-penetrance late-onset disorder.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no available paper reports a validated functional assay showing preserved function for SERPINA1 c.863A>T (p.Glu288Val).	PMID:29232161 PMID:26141072 PMID:6602622
BS4	Not assessed	Not assessed: No affected family members with documented negative variant testing are available to establish lack of segregation.
BP1	Not assessed	Not assessed: missense SERPINA1 disease alleles are documented, but the evidence does not quantify whether truncating variants primarily cause disease.	PMID:29232161
BP2	Not assessed	Not assessed: No proband-level phase testing demonstrates this variant in trans or cis with another pathogenic variant.
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: REVEL 0.692 is above the generic BP4 supporting threshold of 0.29, and SpliceAI cannot substitute for the missense REVEL path.	revel
BP5	Not assessed	Not assessed: no specific case documents this variant alongside an alternate molecular basis for the disease.	clinvar PMID:26141072 PMID:6602622
BP6	Not met	Not met: no exact-variant expert-panel Benign or Likely benign classification is present; ClinVar's available classification is Pathogenic.	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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