rs121909547

Variant names:

• chr1-173914726-G-A
• rs121909547
• NM_000488.4:c.235C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-173914726-G-A
• chr1-173914726-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP3 PP4 PP1_Strong PS4 PM1 PM5

This summary comes from the ClinGen Evidence Repository: The c.235C>T (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 79 (p.Arg79Cys). This variant has been reported in at least 31 probands meeting an antithrombin activity level of <0.8 IU/mL and several more are reported in the literature (PS4_Very Strong; PMID:28300866). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in 18 affected family meioses from 32 families (PP1_Strong; 28300866). One of 50 individuals within 45 families who had a mean AT activity of 53% and AT antigen level of 106%, which is highly specific for hereditary antithrombin deficiencies. The curators confirmed with lead author that most individuals AT levels were confirmed with at least two samples since this is not specified in the publication. The ClinGen Thrombosis VCEP members have agreed that all probands in this paper can be counted at full strength for PP4 (PP4_Supporting; PMID:28300866). The computational predictor REVEL gives a score of 0.743, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant resides within a region, Arg79, of SERPINC1 that would impact heparin binding site residues and is defined as a critical functional domain by the ClinGen Thrombosis VCEP (PMID:2615648; PM1). Another missense variant c.236G>A (p.Arg79His) (ClinVarID:18014) in the same codon has been classified as pathogenic for autosomal dominant hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PS4_Very strong, PM1, PM5, PP3, PP4. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) LINK:https://erepo.genome.network/evrepo/ui/classification/CA210748/MONDO:0013144/084

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 2.56
• Publications: 21 publications found

Genes affected

SERPINC1 (HGNC:775): (serpin family C member 1) The protein encoded by this gene, antithrombin III, is a plasma protease inhibitor and a member of the serpin superfamily. This protein inhibits thrombin as well as other activated serine proteases of the coagulation system, and it regulates the blood coagulation cascade. The protein includes two functional domains: the heparin binding-domain at the N-terminus of the mature protein, and the reactive site domain at the C-terminus. The inhibitory activity is enhanced by the presence of heparin. Numerous mutations have been identified for this gene, many of which are known to cause antithrombin-III deficiency which constitutes a strong risk factor for thrombosis. A reduction in the serum level of this protein is associated with severe cases of Coronavirus Disease 19 (COVID-19). [provided by RefSeq, Sep 2020]

SERPINC1 Gene-Disease associations (from GenCC):

• hereditary antithrombin deficiency

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINC1	NM_000488.4	c.235C>T	p.Arg79Cys	missense_variant	Exon 2 of 7	ENST00000367698.4	NP_000479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINC1	ENST00000367698.4	c.235C>T	p.Arg79Cys	missense_variant	Exon 2 of 7	1	NM_000488.4	ENSP00000356671.3
SERPINC1	ENST00000494024.1	n.461C>T		non_coding_transcript_exon_variant	Exon 3 of 4	3
SERPINC1	ENST00000487183.1	n.-61C>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000477 AC: 12 AN: 251462 AF XY: 0.0000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.000458 AC: 7 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000463 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:6

-

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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 79 of the SERPINC1 protein (p.Arg79Cys). This variant is present in population databases (rs121909547, gnomAD 0.02%). This missense change has been observed in individuals with antithrombin III deficiency (PMID: 3960724, 6582486, 21325262, 24162787, 25837307, 28300866). It has also been observed to segregate with disease in related individuals. This variant is also known as R47C, Arg47Cys, Antithrombin III Toyama, Antithrombin III Alger, and Antithrombin III tours. ClinVar contains an entry for this variant (Variation ID: 18004). 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 not expected to disrupt SERPINC1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 22498748, 27322195). This variant disrupts the p.Arg79 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2615648, 3567355, 7981186, 21264449, 25837307, 26748602, 28607330, 29153735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 19, 2024

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.235C>T (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 79 (p.Arg79Cys). This variant has been reported in at least 31 probands meeting an antithrombin activity level of <0.8 IU/mL and several more are reported in the literature (PS4_Very Strong; PMID:28300866). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in 18 affected family meioses from 32 families (PP1_Strong; 28300866). One of 50 individuals within 45 families who had a mean AT activity of 53% and AT antigen level of 106%, which is highly specific for hereditary antithrombin deficiencies. The curators confirmed with lead author that most individuals AT levels were confirmed with at least two samples since this is not specified in the publication. The ClinGen Thrombosis VCEP members have agreed that all probands in this paper can be counted at full strength for PP4 (PP4_Supporting; PMID:28300866). The computational predictor REVEL gives a score of 0.743, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant resides within a region, Arg79, of SERPINC1 that would impact heparin binding site residues and is defined as a critical functional domain by the ClinGen Thrombosis VCEP (PMID:2615648; PM1). Another missense variant c.236G>A (p.Arg79His) (ClinVarID:18014) in the same codon has been classified as pathogenic for autosomal dominant hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PS4_Very strong, PM1, PM5, PP3, PP4. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) -

Jan 03, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000018004, PMID:6582486, PS1_S). A different missense change at the same codon has been reported to be associated with SERPINC1 related disorder (ClinVar ID: VCV000018015, PMID:2615648,3350974, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.743, PP3_P). A missense variant is a common mechanism associated with Thrombophilia due to antithrombin III deficiency (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000048, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Jul 31, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	.;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.2	.;M
PhyloP100		2.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	.;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.94
MutPred		0.76		Loss of MoRF binding (P = 0.0302);Loss of MoRF binding (P = 0.0302);
MVP		0.96
MPC		1.3
ClinPred		0.68	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.86
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: 2

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

Other links and lift over

dbSNP: rs121909547; hg19: chr1-173883864; COSMIC: COSV62930109; COSMIC: COSV62930109;