chr14-94381049-G-A

Position:

chr14-94381049-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The ENST00000393087.9(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
ENST00000393087.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:8B:1O:1

Conservation

PhyloP100: 2.29

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029084444).

BS2

High Homozygotes in GnomAdExome4 at 5 AR 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/exons	MANE	Protein	UniProt
SERPINA1	NM_000295.5 linkuse as main transcript	c.739C>T	p.Arg247Cys	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.739C>T	p.Arg247Cys	missense_variant	3/5	1	NM_000295.5	ENSP00000376802	P1	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

GnomAD3 exomes

AF:

0.00212

AC:

533

AN:

251358

Hom.:

AF XY:

0.00214

AC XY:

291

AN XY:

135844

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 SAS 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

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000562

Gnomad4 NFE exome

AF:

0.00404

Gnomad4 OTH exome

AF:

0.00162

GnomAD4 genome

AF:

0.00197

AC:

299

AN:

152138

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

129

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000867

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000661

Gnomad4 NFE

AF:

0.00362

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00294

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:4Uncertain:8Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Alpha-1-antitrypsin deficiency

Pathogenic:3Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 24, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 11, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	Dec 08, 2014	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. -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	May 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2023	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); 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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 05, 2022	- -

SERPINA1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 11, 2013

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2017

- -

PI F

Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

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

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

MutationTaster

Benign

0.90

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

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

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

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