NM_000295.5:c.710T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V237V) has been classified 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

Publications

64 publications found

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 Gene-Disease associations (from GenCC):

alpha 1-antitrypsin deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cystic fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SERPINA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 17955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5 link	c.710T>C	p.Val237Ala	missense_variant	Exon 3 of 5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9 link	c.710T>C	p.Val237Ala	missense_variant	Exon 3 of 5	1	NM_000295.5	ENSP00000376802.4		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

GnomAD2 exomes

AF:

0.210

AC:

52480

AN:

250450

AF XY:

0.205

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.561

AC:

18706

AN:

33354

American (AMR)

AF:

0.102

AC:

4546

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6677

AN:

26110

East Asian (EAS)

AF:

0.0120

AC:

476

AN:

39700

South Asian (SAS)

AF:

0.164

AC:

14144

AN:

86154

European-Finnish (FIN)

AF:

0.293

AC:

15553

AN:

53022

Middle Eastern (MID)

AF:

0.167

AC:

940

AN:

5634

European-Non Finnish (NFE)

AF:

0.217

AC:

240825

AN:

1109066

Other (OTH)

AF:

0.218

AC:

13158

AN:

60268

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

12565

25129

37694

50258

62823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8344

16688

25032

33376

41720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.298

AC:

45104

AN:

151240

Hom.:

8923

Cov.:

AF XY:

0.295

AC XY:

21772

AN XY:

73860

show subpopulations

African (AFR)

AF:

0.551

AC:

22584

AN:

40998

American (AMR)

AF:

0.157

AC:

2397

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.260

AC:

900

AN:

3468

East Asian (EAS)

AF:

0.0209

AC:

108

AN:

5158

South Asian (SAS)

AF:

0.152

AC:

722

AN:

4756

European-Finnish (FIN)

AF:

0.298

AC:

3122

AN:

10468

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.213

AC:

14471

AN:

67846

Other (OTH)

AF:

0.252

AC:

530

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1175

2351

3526

4702

5877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

412

824

1236

1648

2060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.235

Hom.:

23061

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

Jun 13, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Benign based on MAF. See note for OMIM entry (which is responsible for the "wit h pathogenic allele" association in dbSNP) -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 03, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alpha-1-antitrypsin deficiency

Benign:3

Dec 08, 2014

Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Inborn genetic diseases

Benign:1

Sep 30, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jul 15, 2016

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

PI M1-ALA213

Benign:1

Jul 15, 2016

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

(source)

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

PhyloP100

-0.18

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over