rs121909554

Positions:

• chr1-173904011-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4 PP1_Moderate PP3 PP4 PM5 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1273C>T variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 425 (p.Arg425Cys). This variant is seen with a total MAF of 0.0000006195, which meets PM2_Supporting. At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:27098529). This variant has been reported in eight more probands with an antithrombin activity level of < 0.8 IU/mL, but not all of them had testing performed on repeated independent samples, crossed immunoelectrophoresis demonstrating an abnormal result or a family history (5.5 points awarded, PS4; PMIDs:22398878, 28300866, 23910795, 4049307, 22481271, 27098529). The variant has been reported to segregate with hereditary antithrombin deficiency in four affected family members, aside from the proband, from one family (PP1_Moderate; PMID:4049307). Another missense variant c.1274G>A (p.Arg425His) (ClinVarID:18019) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). The computational predictor REVEL gives a score of 0.806, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). 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: PS4, PP1_Moderate, PM5, PM2_Supporting, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210762/MONDO:0013144/084

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SERPINC1 ENST00000367698.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.20

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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/exons	MANE	Protein	UniProt
SERPINC1	NM_000488.4	c.1273C>T	p.Arg425Cys	missense_variant	7/7	ENST00000367698.4	NP_000479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINC1	ENST00000367698.4	c.1273C>T	p.Arg425Cys	missense_variant	7/7	1	NM_000488.4	ENSP00000356671	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251344 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 24, 2019	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg425 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been observed in individuals with SERPINC1-related conditions (PMID: 22481271, 28317092), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. This variant has been reported to affect SERPINC1 protein function (PMID: 22481271). This variant has been observed in several individuals with antithrombin deficiency and segregates with disease in at least one family (PMID: 22481271, 27098529, 3179448, 3179448, 4049307). This variant is also known as R393C, Arg393Cys, and Antithrombin III Northwick Park in the literature. ClinVar contains an entry for this variant (Variation ID: 18016). This variant is present in population databases (rs121909554, ExAC 0.01%). This sequence change replaces arginine with cysteine at codon 425 of the SERPINC1 protein (p.Arg425Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 30, 1988	- -
Pathogenic, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Aug 16, 2024	The c.1273C>T variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 425 (p.Arg425Cys). This variant is seen with a total MAF of 0.0000006195, which meets PM2_Supporting. At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID: 27098529). This variant has been reported in eight more probands with an antithrombin activity level of < 0.8 IU/mL, but not all of them had testing performed on repeated independent samples, crossed immunoelectrophoresis demonstrating an abnormal result or a family history (5.5 points awarded, PS4; PMIDs:22398878, 28300866, 23910795, 4049307, 22481271, 27098529). The variant has been reported to segregate with hereditary antithrombin deficiency in four affected family members, aside from the proband, from one family (PP1_Moderate; PMID:4049307). Another missense variant c.1274G>A (p.Arg425His) (ClinVarID:18019) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). The computational predictor REVEL gives a score of 0.806, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). 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: PS4, PP1_Moderate, PM5, PM2_Supporting, PP3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	.;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.3	.;M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	.;D
REVEL	Pathogenic	0.86
Sift	Benign	0.27	.;T
Sift4G	Uncertain	0.0020	D;T
Polyphen		1.0	.;D
Vest4		0.96
MVP		0.92
MPC		1.3
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121909554; hg19: chr1-173873149;