chr1-173903983-A-C

Position:

• chr1-173903983-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5_Supporting PP3 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1301T>G (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of phenylalanine by cystenine at amino acid 434 (p.Phe434Cys). This variant has been reported in 1 proband meeting an antithrombin activity level of < 0.8 IU/mL with repeat testing overtime (PS4_Supporting; PMID:1469094). This variant is absent from gnomAD v3.1.2 and v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.921, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1302C>A (p.Phe434Leu) (ClinVarID:2202884) in the same codon has been classified as likely pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant antithrombin III deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP3, PM2, PM5, PS4_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/CA343772451/MONDO:0013144/084

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 8.52

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.

• 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.
• 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.1301T>G	p.Phe434Cys	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.1301T>G	p.Phe434Cys	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: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Uncertain significance, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Feb 19, 2024	The c.1301T>G (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of phenylalanine by cystenine at amino acid 434 (p.Phe434Cys). This variant has been reported in 1 proband meeting an antithrombin activity level of < 0.8 IU/mL with repeat testing overtime (PS4_Supporting; PMID:1469094). This variant is absent from gnomAD v3.1.2 and v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.921, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1302C>A (p.Phe434Leu) (ClinVarID:2202884) in the same codon has been classified as likely pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant antithrombin III deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP3, PM2, PM5, PS4_Supporting. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	.;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.7	.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.93
MutPred		0.92		.;Loss of stability (P = 0.0613);
MVP		0.97
MPC		1.4
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

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: rs1572084546; hg19: chr1-173873121;