rs4934

Variant names:

• chr14-94614466-G-A
• rs4934
• NM_001085.5:c.25G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-94614466-G-A
• chr14-94614466-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001085.5(SERPINA3):​c.25G>A​(p.Ala9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,613,324 control chromosomes in the GnomAD database, including 182,455 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13832 hom., cov: 31)
  • Exomes 𝑓: 0.48 (168623 hom.)
• Consequence: SERPINA3 NM_001085.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.110
• Publications: 81 publications found

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]

ENSG00000273259 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.4734696E-5).
• BP6: Variant 14-94614466-G-A is Benign according to our data. Variant chr14-94614466-G-A is described in ClinVar as Benign. ClinVar VariationId is 18051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA3	NM_001085.5	c.25G>A	p.Ala9Thr	missense_variant	Exon 2 of 5	ENST00000393078.5	NP_001076.2
SERPINA3	NM_001384672.1	c.25G>A	p.Ala9Thr	missense_variant	Exon 2 of 5		NP_001371601.1
SERPINA3	NM_001384673.1	c.25G>A	p.Ala9Thr	missense_variant	Exon 3 of 6		NP_001371602.1
SERPINA3	NM_001384674.1	c.25G>A	p.Ala9Thr	missense_variant	Exon 3 of 6		NP_001371603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA3	ENST00000393078.5	c.25G>A	p.Ala9Thr	missense_variant	Exon 2 of 5	1	NM_001085.5	ENSP00000376793.3
ENSG00000273259	ENST00000553947.1	n.*851G>A		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000452367.2
ENSG00000273259	ENST00000553947.1	n.*851G>A		3_prime_UTR_variant	Exon 5 of 8	2		ENSP00000452367.2

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61947 AN: 151742 Hom.: 13825 Cov.: 31

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.419

GnomAD2 exomes AF: 0.446 AC: 111980 AN: 251012 AF XY: 0.456

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.236

Gnomad ASJ exome AF: 0.520

Gnomad EAS exome AF: 0.613

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.461

GnomAD4 exome AF: 0.475 AC: 694720 AN: 1461464 Hom.: 168623 Cov.: 51 AF XY: 0.476 AC XY: 345936 AN XY: 727040

African (AFR) AF: 0.223 AC: 7459 AN: 33474

American (AMR) AF: 0.246 AC: 10982 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 13978 AN: 26132

East Asian (EAS) AF: 0.596 AC: 23678 AN: 39700

South Asian (SAS) AF: 0.433 AC: 37366 AN: 86246

European-Finnish (FIN) AF: 0.571 AC: 30458 AN: 53332

Middle Eastern (MID) AF: 0.465 AC: 2678 AN: 5764

European-Non Finnish (NFE) AF: 0.486 AC: 540108 AN: 1111716

Other (OTH) AF: 0.464 AC: 28013 AN: 60378

GnomAD4 genome AF: 0.408 AC: 61968 AN: 151860 Hom.: 13832 Cov.: 31 AF XY: 0.413 AC XY: 30645 AN XY: 74198

African (AFR) AF: 0.238 AC: 9869 AN: 41418

American (AMR) AF: 0.307 AC: 4691 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 1827 AN: 3468

East Asian (EAS) AF: 0.606 AC: 3107 AN: 5126

South Asian (SAS) AF: 0.431 AC: 2068 AN: 4802

European-Finnish (FIN) AF: 0.569 AC: 6002 AN: 10544

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.487 AC: 33066 AN: 67926

Other (OTH) AF: 0.425 AC: 895 AN: 2106

Alfa AF: 0.465 Hom.: 58262

Bravo AF: 0.382

TwinsUK AF: 0.467 AC: 1731

ALSPAC AF: 0.479 AC: 1845

ESP6500AA AF: 0.256 AC: 1129

ESP6500EA AF: 0.477 AC: 4102

ExAC AF: 0.447 AC: 54258

Asia WGS AF: 0.488 AC: 1697 AN: 3478

EpiCase AF: 0.486

EpiControl AF: 0.491

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: MAF

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

ANTICHYMOTRYPSIN SIGNAL PEPTIDE POLYMORPHISM Benign:1

Mar 01, 1997

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

SERPINA3-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.46	T;.;T;.
MetaRNN	Benign	0.000025	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L;L;.;L
PhyloP100		-0.11
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.080	T;T;T;T
Sift4G	Benign	0.21	T;T;T;T
Vest4		0.10
ClinPred		0.010	T
GERP RS		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.16
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4934; hg19: chr14-95080803; COSMIC: COSV67585277; COSMIC: COSV67585277;