rs28929470

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP5BP4BS1_SupportingBS2_Supporting

The NM_000295.5(SERPINA1):c.739C>T(p.Arg247Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,614,004 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R247H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 5 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:8O:1

Conservation

PhyloP100: 2.29

Publications

38 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: Likely_benign. The variant received -2 ACMG points.

PP5

Variant 14-94381049-G-A is Pathogenic according to our data. Variant chr14-94381049-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 17961.

BP4

Computational evidence support a benign effect (MetaRNN=0.029084444). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00197 (299/152138) while in subpopulation NFE AF = 0.00362 (246/67998). AF 95% confidence interval is 0.00325. There are 1 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 5 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5 link	c.739C>T	p.Arg247Cys	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.739C>T	p.Arg247Cys	missense_variant	Exon 3 of 5	1	NM_000295.5	ENSP00000376802.4		P01009-1

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

300

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00362

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00212

AC:

533

AN:

251358

AF XY:

0.00214

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00428

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00319

AC:

4658

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

2255

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000344

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000562

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00404

AC:

4495

AN:

1111992

Other (OTH)

AF:

0.00162

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

234

468

702

936

1170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

182

364

546

728

910

<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:

0.00197

AC:

299

AN:

152138

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

129

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

41514

American (AMR)

AF:

0.000392

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.000661

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00362

AC:

246

AN:

67998

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00305

Hom.:

Bravo

AF:

0.00195

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00287

AC:

349

EpiCase

AF:

0.00278

EpiControl

AF:

0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Alpha-1-antitrypsin deficiency

Pathogenic:4Uncertain:3

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2022

MGZ Medical Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Dec 08, 2014

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

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mildly reduced alpha-1-antitrypsin activity. In practice appears to be associated with mild deficiency. Literature opinion divided. Protein levels may be normal but has a decreased ability to inhibit neutrophil elastase & is frequently seen in patients with respiratory symptoms. -

May 01, 2014

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 13, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jul 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 247 of the SERPINA1 protein (p.Arg247Cys). This variant is present in population databases (rs28929470, gnomAD 0.4%). This missense change has been observed in individual(s) with chronic obstructive pulmonary disease (COPD) and slight decreased A1AT protein levels and alpha 1-antitrypsine (A1AT) deficiency (PMID: 2035534, 22078084). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as allele F or p.Arg223Cys. ClinVar contains an entry for this variant (Variation ID: 17961). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SERPINA1 protein function. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 8912354). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Pathogenic:1Uncertain:2

May 23, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Commonly referred to as the F variant or R223C by alternate nomenclature, and has been reported multiple times in association with normal serum AAT levels when present in the homozygous state and mildly reduced AAT levels when present with another disease-causing SERPINA1 variant (PMID: 2035534, 22078084, 25098359); Homozygosity for R247C may increase susceptibility to elastase-induced lung damage but not emphysema, whereas this variant can be of clinical consequence when in the compound heterozygous state with the Z allele (E366K) (PMID: 25098359); Published functional studies demonstrate a damaging effect on protein function (PMID: 38637533); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 18682522, 26987331, 24713750, 8912354, 25637381, 24082139, 27153395, 22078084, 2035534, 9041988, 15115878, 29882371, 26310624, 23632999, 6306478, Wang2022[Functional Study], 20301692, 31819391, 32181528, 31450843, 26647313, 31661293, 35477570, 37622442, 25098359, 31298815, 37277845, Ramos[Article], 38392031, 39492455, 36658113, 38388492, 39880301, 38659141, DeCurtis2024[CaseReport], 37651384, 38637533) -

Aug 30, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SERPINA1-related disorder

Uncertain:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SERPINA1 c.739C>T variant is predicted to result in the amino acid substitution p.Arg247Cys. This variant has been reported in the literature, but its pathogenicity was not fully understood (Supplementary Table 1 at Amendola et al. 2015. PubMed ID: 25637381; Table S5 at Maxwell et al. 2016. PubMed ID: 27153395). This variant is also known as the F allele or p.Arg223Cys, and is reported to have decreased binding affinity and inhibitory capacity against elastase resulting in lung but not liver disease (Giacopuzzi et al. 2018. PubMed ID: 29882371). This variant is reported in 0.42% of alleles in individuals of European (Non-Finnish) descent), including one homozygous observation. In summary, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Uncertain:1

Oct 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Arg247Cys variant in SERPINA1, also called the F allele, has been identified in 0.4% (35/8600) of European American chromosomes from a large population by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). This vari ant has been reported to affect protein function (Cook 1996) and may contribute to disease when homozygous or when present with other SERPINA1 variants (Ringenb ach 2011). Computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also support an impact to the protein though their accurac y is not known. In summary, additional information is needed to fully assess the clinical significance of this variant. -

Inborn genetic diseases

Uncertain:1

Mar 17, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PI F

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

0.19

BayesDel_addAF

Benign

0.0064

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;D;D;D;D;D;D;D;D;.

Eigen

Benign

-0.016

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.90

.;.;.;D;.;.;.;.;.;D

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.029

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

MetaSVM

Uncertain

0.19

MutationAssessor

Pathogenic

3.7

H;H;H;H;H;H;H;H;H;H

PhyloP100

2.3

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-6.7

D;D;D;D;D;.;D;D;D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

D;D;D;D;D;.;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;.;D;D;D;D

Polyphen

0.99

D;D;D;D;D;D;D;D;D;P

Vest4

0.86

MVP

0.93

MPC

0.17

ClinPred

0.13

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.52

gMVP

0.51

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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