rs709932

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.374G>A(p.Arg125His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,614,092 control chromosomes in the GnomAD database, including 21,879 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 Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1593 hom., cov: 33)

Exomes 𝑓: 0.16 ( 20286 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:2

Conservation

PhyloP100: -0.566

Publications

75 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=0.0047332942).

BP6

Variant 14-94382864-C-T is Benign according to our data. Variant chr14-94382864-C-T is described in ClinVar as Benign. ClinVar VariationId is 17957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5 link	c.374G>A	p.Arg125His	missense_variant	Exon 2 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.374G>A	p.Arg125His	missense_variant	Exon 2 of 5	1	NM_000295.5	ENSP00000376802.4		P01009-1

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19194

AN:

152102

Hom.:

1583

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0391

Gnomad AMI

AF:

0.0936

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.162

Gnomad EAS

AF:

0.220

Gnomad SAS

AF:

0.279

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.161

Gnomad OTH

AF:

0.140

GnomAD2 exomes

AF:

0.160

AC:

40211

AN:

251352

AF XY:

0.171

show subpopulations

Gnomad AFR exome

AF:

0.0332

Gnomad AMR exome

AF:

0.108

Gnomad ASJ exome

AF:

0.162

Gnomad EAS exome

AF:

0.207

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.164

Gnomad OTH exome

AF:

0.166

GnomAD4 exome

AF:

0.161

AC:

235568

AN:

1461870

Hom.:

20286

Cov.:

AF XY:

0.166

AC XY:

120413

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0317

AC:

1061

AN:

33480

American (AMR)

AF:

0.110

AC:

4911

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

4154

AN:

26134

East Asian (EAS)

AF:

0.228

AC:

9039

AN:

39698

South Asian (SAS)

AF:

0.268

AC:

23084

AN:

86258

European-Finnish (FIN)

AF:

0.126

AC:

6747

AN:

53420

Middle Eastern (MID)

AF:

0.189

AC:

1089

AN:

5768

European-Non Finnish (NFE)

AF:

0.158

AC:

175480

AN:

1111992

Other (OTH)

AF:

0.166

AC:

10003

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

13525

27049

40574

54098

67623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6202

12404

18606

24808

31010

<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:

0.126

AC:

19215

AN:

152222

Hom.:

1593

Cov.:

AF XY:

0.128

AC XY:

9500

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0393

AC:

1632

AN:

41532

American (AMR)

AF:

0.121

AC:

1848

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.162

AC:

561

AN:

3468

East Asian (EAS)

AF:

0.221

AC:

1142

AN:

5178

South Asian (SAS)

AF:

0.280

AC:

1349

AN:

4826

European-Finnish (FIN)

AF:

0.121

AC:

1284

AN:

10592

Middle Eastern (MID)

AF:

0.228

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.161

AC:

10937

AN:

68012

Other (OTH)

AF:

0.147

AC:

310

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

844

1688

2532

3376

4220

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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:

0.153

Hom.:

6733

Bravo

AF:

0.117

TwinsUK

AF:

0.160

AC:

593

ALSPAC

AF:

0.150

AC:

578

ESP6500AA

AF:

0.0363

AC:

160

ESP6500EA

AF:

0.165

AC:

1421

ExAC

AF:

0.163

AC:

19806

Asia WGS

AF:

0.237

AC:

825

AN:

3478

EpiCase

AF:

0.169

EpiControl

AF:

0.172

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alpha-1-antitrypsin deficiency

Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 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. -

Jan 27, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 25, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 06, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg125His in exon 4 of SERPINA1: This variant is not expected to have clinical significance because it has been identified in 27% (4488/16512) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs709932). -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22426792, 27153395, 2339709, 20981092, 14551891, 2901226) -

Inborn genetic diseases

Benign:1

Aug 02, 2017

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 M4

Other:1

Jul 15, 2016

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

PI M2

Other:1

Jul 15, 2016

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.17

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.13

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

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.10

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

MetaRNN

Benign

0.0047

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.2

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

PhyloP100

-0.57

PrimateAI

Benign

0.18

PROVEAN

Benign

3.1

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

REVEL

Benign

0.24

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

B;B;B;B;B;B;B;B;B;B;.;.;.

Vest4

0.0070

MPC

0.051

ClinPred

0.0016

GERP RS

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.075

gMVP

0.27

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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