rs28931570

Variant names:

• chr14-94383051-G-A
• rs28931570
• NM_000295.5:c.187C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-94383051-G-A
• chr14-94383051-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_Strong BP4 BS2_Supporting

The NM_000295.5(SERPINA1):​c.187C>T​(p.Arg63Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,613,714 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R63G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 2.88
• Publications: 36 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PP5: Variant 14-94383051-G-A is Pathogenic according to our data. Variant chr14-94383051-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11158815). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000295.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	NM_000295.5	MANE Select	c.187C>T	p.Arg63Cys	missense	Exon 2 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.187C>T	p.Arg63Cys	missense	Exon 2 of 5	NP_001002235.1
	SERPINA1	NM_001002236.3		c.187C>T	p.Arg63Cys	missense	Exon 4 of 7	NP_001002236.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.187C>T	p.Arg63Cys	missense	Exon 2 of 5	ENSP00000376802.4
	SERPINA1	ENST00000355814.8	TSL:1	c.187C>T	p.Arg63Cys	missense	Exon 2 of 5	ENSP00000348068.4
	SERPINA1	ENST00000393088.8	TSL:1	c.187C>T	p.Arg63Cys	missense	Exon 4 of 7	ENSP00000376803.4

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 228 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00106 AC: 266 AN: 251314 AF XY: 0.00113

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00182 AC: 2653 AN: 1461366 Hom.: 7 Cov.: 32 AF XY: 0.00171 AC XY: 1246 AN XY: 726852

African (AFR) AF: 0.000329 AC: 11 AN: 33470

American (AMR) AF: 0.000492 AC: 22 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39680

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00225 AC: 2497 AN: 1111550

Other (OTH) AF: 0.00174 AC: 105 AN: 60382

GnomAD4 genome AF: 0.00150 AC: 228 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74510

African (AFR) AF: 0.000601 AC: 25 AN: 41578

American (AMR) AF: 0.000915 AC: 14 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00272 AC: 185 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00173 Hom.: 1

Bravo AF: 0.00154

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.000972 AC: 118

EpiCase AF: 0.00267

EpiControl AF: 0.00302

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:11

Dec 08, 2014

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Reduced enzyme activity

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

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 63 of the SERPINA1 protein (p.Arg63Cys). This variant is present in population databases (rs28931570, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with alpha 1-antitrypsin deficiency when in combination with the p.Glu366Lys (Pi*Z) variant. Individuals with this missense change and the p.Glu288Val (Pi*S) variant have been reported with mild or no deficiency of alpha 1-antitrypsin (PMID: 2606478, 10194472, 21752289, 22912357, 24713750). This variant is also known as Arg39Cys and the I allele. ClinVar contains an entry for this variant (Variation ID: 17974). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINA1 protein function. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 10194472). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Jul 15, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The SERPINA1 c.187C>T (p.R63C) variant (also known as the I allele) is a mildly deficient variant. Alpha-1 antitrypsin deficiency has been reported in individuals homozygous for the SERPINA1 I allele, or if the I allele is present with a more severe SERPINA1 variant (i.e. SERPINA1 c.1096G>A, p.E366K, also known as the Z allele) (PMID: 2606478, 10194472; 22912357).

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Jun 24, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 17, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SERPINA1 c.187C>T (p.Arg63Cys) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251314 control chromosomes in the gnomAD database, including 1 homozygote. c.187C>T (also known as Arg39Cys and as I allele) has been reported in the literature in multiple individuals affected with Alpha-1-Antitrypsin Deficiency (e.g. Mahadeva_1999, Carroll_2011, Donato_2012, Gupta_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant exhibits decreased stability, and forms aberrant disulphide bonds leading to reduced secretion of a1-antitrypsin (Mahadeva_1999, Jung_2004, Ronzoni_2016). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as other. Based on the evidence outlined above, the variant was classified as pathogenic.

May 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SERPINA1 c.187C>T (p.Arg63Cys) missense variant, more commonly known as p.Arg39Cys or the protease inhibitor (PI) type I variant (PI*I), is widely reported in the literature. Across a selection of the available literature, the p.Arg63Cys variant has been identified in a compound heterozygous state with a known pathogenic variant in at least 156 individuals with alpha-1 antitrypsin deficiency (Baur et al. 1987; Seri et al., 1992; Mahadeva et al. 1999; Ferrarotti et al., 2007; Zorzetto et al., 2008; Carroll et al., 2011; Donato et al., 2012; Suh-Lailam et al. 2014; Duk et al.2016; Silva et al. 2016). The p.Arg63Cys variant is reported at a frequency of 0.00298 in the European population of the 1000 Genomes Project. Mahadeva et al. (1999) performed an in vitro functional study and discovered the p.Arg63Cys variant protein is conformationally unstable and forms polymer chains, while the wild type SERPINA1 protein remains monomeric. The variant is thought to have a mild effect on the SERPINA1 protein and likely requires the contribution of a strongly pathogenic variant to cause disease. Based on the collective evidence, the p.Arg63Cys variant is classified as pathogenic for alpha-1 antitrypsin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;For recessive disorders, detected in trans with a pathogenic variant.

not provided Pathogenic:3

Aug 14, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SERPINA1: PM3:Very Strong, PS3, PM2:Supporting

Apr 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the R63C variant impairs protein secretion by forming aberrant disulfide bonds (Ronzoni et al., 2016); 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: 24713750, 29882371, 26987331, 24055113, 25637381, 21228398, 23632999, 27296815, 30487145, 31447099, 31589614, 2606478, 26647313, 34426522, 31980526)

SERPINA1-related disorder Pathogenic:1

Aug 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SERPINA1 c.187C>T variant is predicted to result in the amino acid substitution p.Arg63Cys. This variant is also known as p.Arg39Cys and as the protease inhibitor (PI) type I variant (PI*I). It has been reported as a mild Alpha-1 antitrypsin deficiency variant that requires the presence of a second strong deficiency variant to cause disease (Amendola et al. 2015. PubMed ID: 25637381; Baur and Bencze. 1987. PubMed ID: 3496639; Mahadeva et al. 1999. PubMed ID: 10194472; Silva et al. 2016. PubMed ID: 27296815; Giacopuzzi et al. 2018. PubMed ID: 29882371). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD. We classify this variant as likely pathogenic.

PI I Other:1

Jul 15, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		2.9
PrimateAI	Benign	0.23	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.84
MVP		1.0
MPC		0.20
ClinPred		0.092	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.40
gMVP		0.59
Mutation Taster		=44/56	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28931570; hg19: chr14-94849388; COSMIC: COSV63345474; COSMIC: COSV63345474;