14-94614466-G-A

Position:

chr14-94614466-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.41 ( 13832 hom., cov: 31)

Exomes 𝑓: 0.48 ( 168623 hom. )

Consequence

SERPINA3
NM_001085.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.110

Variant links:

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]

SERPINA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 18051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94614466-G-A is described in Lovd as [Benign].

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/exons	MANE
SERPINA3	NM_001085.5 linkuse as main transcript	c.25G>A	p.Ala9Thr	missense_variant	2/5	ENST00000393078.5
SERPINA3	NM_001384672.1 linkuse as main transcript	c.25G>A	p.Ala9Thr	missense_variant	2/5
SERPINA3	NM_001384673.1 linkuse as main transcript	c.25G>A	p.Ala9Thr	missense_variant	3/6
SERPINA3	NM_001384674.1 linkuse as main transcript	c.25G>A	p.Ala9Thr	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA3	ENST00000393078.5 linkuse as main transcript	c.25G>A	p.Ala9Thr	missense_variant	2/5	1	NM_001085.5	P1	P01011-1

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

61947

AN:

151742

Hom.:

13825

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.446

AC:

111980

AN:

251012

Hom.:

26860

AF XY:

0.456

AC XY:

61827

AN XY:

135668

show subpopulations

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 SAS exome

AF:

0.428

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.:

AF XY:

0.476

AC XY:

345936

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.223

Gnomad4 AMR exome

AF:

0.246

Gnomad4 ASJ exome

AF:

0.535

Gnomad4 EAS exome

AF:

0.596

Gnomad4 SAS exome

AF:

0.433

Gnomad4 FIN exome

AF:

0.571

Gnomad4 NFE exome

AF:

0.486

Gnomad4 OTH exome

AF:

0.464

GnomAD4 genome

AF:

0.408

AC:

61968

AN:

151860

Hom.:

13832

Cov.:

AF XY:

0.413

AC XY:

30645

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.238

Gnomad4 AMR

AF:

0.307

Gnomad4 ASJ

AF:

0.527

Gnomad4 EAS

AF:

0.606

Gnomad4 SAS

AF:

0.431

Gnomad4 FIN

AF:

0.569

Gnomad4 NFE

AF:

0.487

Gnomad4 OTH

AF:

0.425

Alfa

AF:

0.477

Hom.:

43204

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

LINK: link

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: MAF -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

ANTICHYMOTRYPSIN SIGNAL PEPTIDE POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Mar 01, 1997

- -

SERPINA3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

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

LIST_S2

Benign

0.46

T;.;T;.

MetaRNN

Benign

0.000025

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

L;L;.;L

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.30

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

Polyphen

0.12

B;B;.;B

Vest4

0.10

MPC

0.014

ClinPred

0.010

GERP RS

-0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.055

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over