Variant classification summary

NM_000295.5:c.1096G>A

SERPINA1 · NP_000286.3:p.(Glu366Lys) · NM_000295.5

GRCh37: chr14:94844947 C>T · GRCh38: chr14:94378610 C>T

Gene: SERPINA1 Transcript: NM_000295.5

Final call

Likely Pathogenic

PS1 strong PS3 supporting PP3 supporting

Variant details

Gene

SERPINA1

Transcript

NM_000295.5

Protein

NP_000286.3:p.(Glu366Lys)

gnomAD AF

0.01586291664549959 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS1 strong identifies p.Glu366Lys as the established SERPINA1 Z substitution.

2

Likely Pathogenic: PS3 supporting shows reduced serum alpha-1-antitrypsin, intracellular accumulation, and liver injury in a controlled transgenic-mouse study.

3

Likely Pathogenic: PP3 supporting is met because REVEL 0.686 exceeds the generic threshold of 0.644.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus two supporting pathogenic criteria yields Likely Pathogenic.

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: p.Glu366Lys is the established pathogenic SERPINA1 Z substitution p.Glu342Lys, and SpliceAI max delta is 0.00.	PMID:19164889 PMID:3264419 spliceai
PS2	Not assessed	Not assessed: no documented proband phenotype, family-history status, or confirmed maternity and paternity testing is available for this variant.
PS3	Met	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.	PMID:3264419
PS4	Not assessed	Not assessed: no affected-case frequency or control comparison was available to calculate the required OR/RR >5.0 with a confidence interval excluding 1.	PMID:24121147 PMID:7045697 gnomad_v4
PM1	Not assessed	Not assessed: no approved domain or hotspot evidence establishes residue 366 as a critical region, and Cancer Hotspots reports no statistically significant E366 hotspot.	hotspots cosmic
PM2	Not met	Not met: gnomAD v4.1 grpmax FAF 0.0191827 exceeds the generic PM2 threshold of 0.0001 by more than two orders of magnitude.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no documented affected proband, pathogenic allele in trans, or parental/offspring phase testing establishes the required allelic observation.	clinvar gnomad_v4
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 change at residue 366 is documented; the available papers describe the same p.Glu366Lys Z variant.	pm5_candidates PMID:19164889 PMID:3264419
PM6	Not assessed	Not assessed: no report states that this variant is de novo, with or without parental maternity and paternity confirmation.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or family genotype–phenotype segregation observations are documented for this variant.
PP2	Not assessed	Not assessed: no validated gene-wide benign-missense-rate analysis is available, while the variant has gnomAD v4.1 AF 0.0158629 and 263 homozygotes.	gnomad_v4 PMID:19164889
PP3	Met	Met at supporting strength: REVEL 0.686 meets 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 was available to establish a highly specific single-gene presentation.	PMID:24121147 PMID:19164889 PMID:3264419
PP5	Not met	Not met: ClinVar shows zero expert-panel submissions for the exact variant, so no qualifying pathogenic source triggers PP5.	clinvar
BA1	Not met	Not met: gnomAD grpmax FAF 0.0191827 is below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:19164889
BS1	Not met	Not met: q=0.0191827 gives q²=0.00036798, approximately 1 in 2,718, within the reported 1-in-2,000-to-3,500 ZZ prevalence range.	gnomad_v4 gnomad_v2 PMID:24121147 PMID:19164889
BS2	N/A	Not applicable: gnomAD reports 263 homozygotes, but the disorder is not established as fully penetrant at an early age for BS2.	gnomad_v2 gnomad_v4 PMID:19164889 PMID:24121147
BS3	Not met	Not met: the variant-specific mouse study showed reduced serum AAT and hepatic accumulation with liver injury, not preserved protein function or normal splicing.	PMID:3264419
BS4	Not assessed	Not assessed: no tested affected relative lacking the variant is documented, so lack of segregation cannot be established.
BP1	Not met	Not met: the established SERPINA1 Z disease allele is pathogenic missense p.Glu342Lys, not evidence of a primarily truncating disease mechanism.	PMID:19164889 PMID:3264419
BP2	Not assessed	Not assessed: no phase-resolved observation shows the variant in trans or cis with a pathogenic variant under the BP2 definitions.	clinvar gnomad_v4
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 0.686 exceeds the generic BP4 supporting threshold of <=0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: no documented case links this exact variant to disease caused by a confirmed alternate molecular basis.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely-benign classification was identified.	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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