1-173903972-T-C

Position:

• chr1-173903972-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1312A>G (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 438 (p.Arg438Gly). The variant is absent from gnomAD v2.1.1, v3.1, v4.0.0 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting. The computational predictor REVEL gives a score of 0.752, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. This variant has been reported in a single patient with an antithrombin activity level of 45-53% meeting the SERPINC1-phenotypic criteria (AT level of <0.8 IU/mL) (PS4_Supporting). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: PP3, PM2_Supporting, PS4_ Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343772388/MONDO:0013144/084

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 1.64

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 3 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.
• 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.1312A>G	p.Arg438Gly	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.1312A>G	p.Arg438Gly	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:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Uncertain:1

Uncertain significance, reviewed by expert panel

curation

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

Feb 19, 2024

The c.1312A>G (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 438 (p.Arg438Gly). The variant is absent from gnomAD v2.1.1, v3.1, v4.0.0 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting. The computational predictor REVEL gives a score of 0.752, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. This variant has been reported in a single patient with an antithrombin activity level of 45-53% meeting the SERPINC1-phenotypic criteria (AT level of <0.8 IU/mL) (PS4_Supporting). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: PP3, PM2_Supporting, PS4_ Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.7	.;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.0	.;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.015	.;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.99	.;D
Vest4		0.77
MutPred		0.92		.;Loss of MoRF binding (P = 0.0077);
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.89
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-173873110;