1-173904010-C-T

Position:

• chr1-173904010-C-T

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PS4 PP1_Moderate PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1274G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 425 (p.Arg425His; legacy nomenclature p.R393H aka Antithrombin Glasgow). The computational predictor REVEL gives a score of 0.806, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. This variant is at extremely low frequency (Total: 0.000003979, European (non-Finnish): 0.000008798) in gnomAD v2.1.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting (MAF <2.0 X 10-5). This variant has been reported in at least 16 probands in the literature with AT deficiency meeting PP4 and PS4_VeryStrong (PMID:26134363; 27766527; 28607330; 28300866; 3179448). Additionally, this variant has been report in at least 4 meioses across 14 families meeting PP1_Moderate. In summary, based on the evidence available at this time, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Moderate, PP3, PP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210766/MONDO:0013144/084

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 ENST00000367698.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.22

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 9 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.
• 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.1274G>A	p.Arg425His	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.1274G>A	p.Arg425His	missense_variant	7/7	1	NM_000488.4	ENSP00000356671	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251350 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:3

Pathogenic, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Sep 21, 2023	The c.1274G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 425 (p.Arg425His; legacy nomenclature p.R393H aka Antithrombin Glasgow). The computational predictor REVEL gives a score of 0.806, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. This variant is at extremely low frequency (Total: 0.000003979, European (non-Finnish): 0.000008798) in gnomAD v2.1.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting (MAF <2.0 X 10-5). This variant has been reported in at least 16 probands in the literature with AT deficiency meeting PP4 and PS4_VeryStrong (PMID: 26134363; 27766527; 28607330; 28300866; 3179448). Additionally, this variant has been report in at least 4 meioses across 14 families meeting PP1_Moderate. In summary, based on the evidence available at this time, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Moderate, PP3, PP4, PM2_Supporting. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1989	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2020	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg425Cys amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22481271, 27098529, 3179448, 4049307). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect SERPINC1 protein function (PMID: 22481271). This variant has been observed in individual(s) with antithrombin III deficiency (PMID: 3179448, 22481271, 28317092, 28607330, Invitae). This variant is also known as Arg393His and ATIII Glasgow in the literature. ClinVar contains an entry for this variant (Variation ID: 18019). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 425 of the SERPINC1 protein (p.Arg425His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.1	.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.9	.;D
REVEL	Pathogenic	0.81
Sift	Benign	0.28	.;T
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	.;D
Vest4		0.88
MutPred		0.86		.;Loss of methylation at R425 (P = 0.0245);
MVP		0.85
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		0.92
gMVP		0.85

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: rs121909549; hg19: chr1-173873148;