rs28929470

chr14-94381049-G-Achr14-94381049-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:7 B:1 O:1
• Conservation: PhyloP100: 2.29

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029084444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.739C>T	p.Arg247Cys	missense_variant	3/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.739C>T	p.Arg247Cys	missense_variant	3/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152020 Hom.: 1 Cov.: 32

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.: 1 AF XY: 0.00214 AC XY: 291 AN XY: 135844

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.: 5 Cov.: 31 AF XY: 0.00310 AC XY: 2255 AN XY: 727228

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.: 1 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74364

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.: 3

Bravo AF: 0.00195

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00287 AC: 349

EpiCase AF: 0.00278

EpiControl AF: 0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:7 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:3 Uncertain:3 Benign:1

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, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 08, 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 (Okayama et al., 1991; Ringenbach et al., 2011; Sinden et al., 2014); 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) (Sinden et al., 2014); 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, 25098359, 2035534, 9041988, 15115878, 29882371, 26310624, 23632999, 6306478, Wang2022[Functional Study], 20301692, 31819391, 32181528, 31450843, 26647313, 31661293, 35477570) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2018	- -

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	T
BayesDel_noAF	Pathogenic	0.24
Cadd	Benign	23
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	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.029	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.19	D
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	T
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	T
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

Other links and lift over

dbSNP: rs28929470; hg19: chr14-94847386; COSMIC: COSV63345392; COSMIC: COSV63345392;