chr1-173903969-G-A

Position:

• chr1-173903969-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1315C>T (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of proline by serine at amino acid 439 (p.Pro439Ser). This variant is completely absent from gnomAD v2.1.1, v3.1.2 and v4.0.0 (PM2_Supporting). One proband with this variant is reported in the literature but cannot be counted towards PS4 as the AT levels of this patient are not published. The computational predictor REVEL gives a score of 0.901, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1315C>A (p.Pro439Thr) (ClinVarID:627228) in the same codon has been classified as pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PM5, PP3, PM2_Supporting. (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/CA343772365/MONDO:0013144/084

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 9.14

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1315C>T	p.Pro439Ser	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.1315C>T	p.Pro439Ser	missense_variant	7/7	1	NM_000488.4	ENSP00000356671	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Uncertain:2

Uncertain significance, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Feb 19, 2024	The c.1315C>T (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of proline by serine at amino acid 439 (p.Pro439Ser). This variant is completely absent from gnomAD v2.1.1, v3.1.2 and v4.0.0 (PM2_Supporting). One proband with this variant is reported in the literature but cannot be counted towards PS4 as the AT levels of this patient are not published. The computational predictor REVEL gives a score of 0.901, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1315C>A (p.Pro439Thr) (ClinVarID:627228) in the same codon has been classified as pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PM5, PP3, PM2_Supporting. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 13, 2021	This sequence change replaces proline with serine at codon 439 of the SERPINC1 protein (p.Pro439Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SERPINC1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Pro439 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Deep venous thrombosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.2	.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.84
MutPred		0.95		.;Gain of MoRF binding (P = 0.0394);
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.98

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: rs1487411568; hg19: chr1-173873107; COSMIC: COSV62930470; COSMIC: COSV62930470;