Variant classification summary

NM_001127701.1:c.1096G>A

SERPINA1 · NP_001121173.1:p.(Glu366Lys) · NM_001127701.1

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

Gene: SERPINA1 Transcript: NM_001127701.1

Final call

VUS

PP3 supporting

Variant details

Gene

SERPINA1

Transcript

NM_001127701.1

Protein

NP_001121173.1:p.(Glu366Lys)

gnomAD AF

0.01586291664549959 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PP3 supporting is met because REVEL is 0.686, above the adjudicated threshold of 0.644.

2

VUS: one supporting criterion does not meet any generic ACMG pathogenic or benign combination rule.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not satisfy any Likely Pathogenic, Pathogenic, Likely Benign, or Benign rule, so the final call is VUS.

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: ClinVar reports the same c.1096G>A variant, but no alternate nucleotide change producing p.Glu366Lys is documented.	clinvar
PS2	Not assessed	Not assessed: paternal origin is recorded, but confirmed maternity, confirmed paternity, affected-proband status, and absent family history are not documented.	clinvar
PS3	Not assessed	Not assessed: available functional studies test the distinct E342K variant, not the queried E366K substitution, so no variant-specific damaging assay result is available.	PMID:25738741 PMID:27246852
PS4	Not assessed	Not assessed: no exact-variant affected-versus-control counts or case frequency were available to compute the required OR/RR >5.0 with a confidence interval excluding 1.0.	gnomad_v4 PMID:15685488 PMID:15978931 PMID:18183837 PMID:23169492
PM1	Not met	Not met: cancerhotspots.org found no statistically significant E366 hotspot, and no established critical domain with absent benign variation is documented.
PM2	Not met	Not met: gnomAD v4.1 all-comers frequency is 1.58629%, far above the PM2 supporting threshold of 0.01%.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation, pathogenic partner variant, inheritance mode, or parental phase establishes the required in-trans evidence.
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: the residue-366 comparator search found zero alternative missense candidates established as pathogenic.	pm5_candidates
PM6	Not assessed	Not assessed: no assumed de novo event is documented, and the available paternal-origin entry lacks the proband and parental-testing details required for PM6.	clinvar
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, segregation counts, or variant-specific family co-segregation data are documented.	clinvar
PP2	Not assessed	Not assessed: gnomAD v4.1 frequency is 1.58629%, but no gene-level benign-missense rate and missense-mechanism evidence are supplied.	gnomad_v4
PP3	Met	Met at supporting strength: missense REVEL score 0.686 exceeds the PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history description was available to establish a highly specific single-gene disease presentation.
PP5	Not met	Not met: ClinVar shows zero expert-panel submissions for the exact variant, and ordinary laboratory labels cannot trigger PP5.	PMID:15685488 PMID:25738741
BA1	Not met	Not met: gnomAD v4.1 all-comers frequency is 1.58629%, below the 5% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: overall frequency is 1.58629%, but reduced and age-dependent penetrance requires a maximum-credible-frequency calculation before BS1 can be applied.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 263 homozygotes, but aggregate counts do not prove healthy adult status or early full penetrance.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: available functional studies test E342K rather than E366K, providing no variant-specific evidence of preserved protein function or normal splicing.	PMID:25738741 PMID:27246852
BS4	Not assessed	Not assessed: no affected relatives without the variant, pedigree, non-segregation count, or evaluation for phenocopy and alternative familial variants is documented.	clinvar
BP1	Not assessed	Not assessed: null alleles are described, but no validated comparison shows that truncating variants primarily cause SERPINA1 disease.
BP2	Not assessed	Not assessed: no phase-resolved observation shows the variant in trans or cis with a pathogenic variant under the BP2 inheritance-specific conditions.
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 0.686 is above the BP4 supporting cutoff of 0.29, so it does not support no impact.	revel
BP5	Not assessed	Not assessed: no case-level alternate molecular diagnosis was documented for the patient carrying this variant.
BP6	Not met	Not met: ClinVar shows zero expert-panel submissions for the exact variant, and no verified exact-variant reputable benign report was found.
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.