chr1-173903891-A-G

Variant names:

• chr1-173903891-A-G
• rs1572084425
• NM_000488.4:c.1393T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_Supporting PM4

This summary comes from the ClinGen Evidence Repository: The c.1393T>C variant is predicted to cause a change in the length of the protein (p.Ter465Gln) due to being a stop-loss variant in a non-repeat region (PM4). This variant is absent from gnomAD v2.1.1, v3.1.2 and v4.1.0 (PM2_Supporting). 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: PM4, PM2_Supporting. ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; 2/21/25. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343771985/MONDO:0013144/084

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 stop_lost
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 5.46

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.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINC1	NM_000488.4	c.1393T>C	p.Ter465Glnext*?	stop_lost	Exon 7 of 7	ENST00000367698.4	NP_000479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINC1	ENST00000367698.4	c.1393T>C	p.Ter465Glnext*?	stop_lost	Exon 7 of 7	1	NM_000488.4	ENSP00000356671.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:1 Uncertain:1

Feb 21, 2025

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1393T>C variant is predicted to cause a change in the length of the protein (p.Ter465Gln) due to being a stop-loss variant in a non-repeat region (PM4). This variant is absent from gnomAD v2.1.1, v3.1.2 and v4.1.0 (PM2_Supporting). 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: PM4, PM2_Supporting. ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; 2/21/25. -

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.79
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.63	D
Vest4		0.26
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1572084425; hg19: chr1-173873029;