rs17826465

chr14-94614744-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001085.5(SERPINA3):c.303A>G(p.Lys101=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.098 in 1,614,086 control chromosomes in the GnomAD database, including 8,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (536 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8109 hom.)
• Consequence: SERPINA3 NM_001085.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.311

Genes affected

SERPINA3 (HGNC:16): (serpin family A member 3) The protein encoded by this gene is a member of the serpin family of proteins, a group of proteins that inhibit serine proteases. This gene is one in a cluster of serpin genes located on the q arm of chromosome 14. Polymorphisms in this protein appear to be tissue specific and influence protease targeting. Variations in this protein's sequence have been implicated in Alzheimer's disease, and deficiency of this protein has been associated with liver disease. Mutations have been identified in patients with Parkinson disease and chronic obstructive pulmonary disease. [provided by RefSeq, Jun 2020]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-94614744-A-G is Benign according to our data. Variant chr14-94614744-A-G is described in ClinVar as [Benign]. Clinvar id is 403428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.311 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA3	NM_001085.5	c.303A>G	p.Lys101=	synonymous_variant	2/5	ENST00000393078.5
SERPINA3	NM_001384672.1	c.303A>G	p.Lys101=	synonymous_variant	2/5
SERPINA3	NM_001384673.1	c.303A>G	p.Lys101=	synonymous_variant	3/6
SERPINA3	NM_001384674.1	c.303A>G	p.Lys101=	synonymous_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA3	ENST00000393078.5	c.303A>G	p.Lys101=	synonymous_variant	2/5	1	NM_001085.5	P1

Frequencies

GnomAD3 genomes AF: 0.0730 AC: 11111 AN: 152102 Hom.: 539 Cov.: 32

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.0751

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.0713

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0891

GnomAD3 exomes AF: 0.0809 AC: 20330 AN: 251304 Hom.: 1043 AF XY: 0.0836 AC XY: 11352 AN XY: 135810

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.0592

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.00272

Gnomad SAS exome AF: 0.0792

Gnomad FIN exome AF: 0.0439

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.0959

GnomAD4 exome AF: 0.101 AC: 147080 AN: 1461866 Hom.: 8109 Cov.: 36 AF XY: 0.100 AC XY: 73043 AN XY: 727230

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.0607

Gnomad4 ASJ exome AF: 0.0993

Gnomad4 EAS exome AF: 0.00161

Gnomad4 SAS exome AF: 0.0780

Gnomad4 FIN exome AF: 0.0475

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.0729 AC: 11100 AN: 152220 Hom.: 536 Cov.: 32 AF XY: 0.0698 AC XY: 5195 AN XY: 74450

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.0750

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.0713

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.0891

Alfa AF: 0.107 Hom.: 1639

Bravo AF: 0.0737

Asia WGS AF: 0.0560 AC: 194 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

SERPINA3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.4
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17826465; hg19: chr14-95081081; COSMIC: COSV67585529; COSMIC: COSV67585529;