rs6647

Positions:

chr14-94381078-A-G

Variant summary

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

The NM_000295.5(SERPINA1):c.710T>C(p.Val237Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,609,248 control chromosomes in the GnomAD database, including 47,211 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8923 hom., cov: 30)

Exomes 𝑓: 0.22 ( 38288 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.183

Variant links:

Genes affected

SERPINA1 (HGNC:8941): (serpin family A member 1) The protein encoded by this gene is a serine protease inhibitor belonging to the serpin superfamily whose targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. This protein is produced in the liver, the bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut. Defects in this gene are associated with chronic obstructive pulmonary disease, emphysema, and chronic liver disease. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

SERPINA1 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=1.7623495E-5).

BP6

Variant 14-94381078-A-G is Benign according to our data. Variant chr14-94381078-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 17955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94381078-A-G is described in Lovd as [Benign]. Variant chr14-94381078-A-G is described in Lovd as [Likely_benign]. Variant chr14-94381078-A-G is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA1	NM_000295.5 linkuse as main transcript	c.710T>C	p.Val237Ala	missense_variant	3/5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9 linkuse as main transcript	c.710T>C	p.Val237Ala	missense_variant	3/5	1	NM_000295.5	ENSP00000376802	P1	P01009-1

Frequencies

GnomAD3 genomes

AF:

0.298

AC:

45061

AN:

151122

Hom.:

8912

Cov.:

show subpopulations

Gnomad AFR

AF:

0.551

Gnomad AMI

AF:

0.251

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.260

Gnomad EAS

AF:

0.0209

Gnomad SAS

AF:

0.153

Gnomad FIN

AF:

0.298

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.213

Gnomad OTH

AF:

0.255

GnomAD3 exomes

AF:

0.210

AC:

52480

AN:

250450

Hom.:

7248

AF XY:

0.205

AC XY:

27722

AN XY:

135346

show subpopulations

Gnomad AFR exome

AF:

0.558

Gnomad AMR exome

AF:

0.0941

Gnomad ASJ exome

AF:

0.259

Gnomad EAS exome

AF:

0.0213

Gnomad SAS exome

AF:

0.160

Gnomad FIN exome

AF:

0.299

Gnomad NFE exome

AF:

0.218

Gnomad OTH exome

AF:

0.212

GnomAD4 exome

AF:

0.216

AC:

315025

AN:

1458008

Hom.:

38288

Cov.:

AF XY:

0.213

AC XY:

154538

AN XY:

725512

show subpopulations

Gnomad4 AFR exome

AF:

0.561

Gnomad4 AMR exome

AF:

0.102

Gnomad4 ASJ exome

AF:

0.256

Gnomad4 EAS exome

AF:

0.0120

Gnomad4 SAS exome

AF:

0.164

Gnomad4 FIN exome

AF:

0.293

Gnomad4 NFE exome

AF:

0.217

Gnomad4 OTH exome

AF:

0.218

GnomAD4 genome

AF:

0.298

AC:

45104

AN:

151240

Hom.:

8923

Cov.:

AF XY:

0.295

AC XY:

21772

AN XY:

73860

show subpopulations

Gnomad4 AFR

AF:

0.551

Gnomad4 AMR

AF:

0.157

Gnomad4 ASJ

AF:

0.260

Gnomad4 EAS

AF:

0.0209

Gnomad4 SAS

AF:

0.152

Gnomad4 FIN

AF:

0.298

Gnomad4 NFE

AF:

0.213

Gnomad4 OTH

AF:

0.252

Alfa

AF:

0.223

Hom.:

9567

Bravo

AF:

0.299

TwinsUK

AF:

0.225

AC:

833

ALSPAC

AF:

0.217

AC:

837

ESP6500AA

AF:

0.541

AC:

2382

ESP6500EA

AF:

0.212

AC:

1821

ExAC

AF:

0.221

AC:

26873

Asia WGS

AF:

0.100

AC:

351

AN:

3478

EpiCase

AF:

0.202

EpiControl

AF:

0.200

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 13, 2013	Benign based on MAF. See note for OMIM entry (which is responsible for the "wit h pathogenic allele" association in dbSNP) -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2023	- -

Alpha-1-antitrypsin deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	curation	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	Dec 08, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PI, M1A

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

PI M1-ALA213

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.0090

DANN

Benign

0.31

DEOGEN2

Benign

0.12

T;T;T;T;T;T;T;T;T;.

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.0056

.;.;.;T;.;.;.;.;.;T

MetaRNN

Benign

0.000018

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.63

N;N;N;N;N;N;N;N;N;N

MutationTaster

Benign

1.0

P;P;P;P;P;P;P;P;P

PrimateAI

Benign

0.21

PROVEAN

Benign

1.1

N;N;N;N;N;.;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.60

T;T;T;T;T;.;T;T;T;T

Sift4G

Benign

0.60

T;T;T;T;T;.;T;T;T;T

Polyphen

0.0

B;B;B;B;B;B;B;B;B;B

Vest4

0.023

MPC

0.050

ClinPred

0.0091

GERP RS

-9.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.068

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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