NM_000488.4:c.1376C>A

Variant names:

• chr1-173903908-G-T
• rs1572084448
• NM_000488.4:c.1376C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2_Supporting PS4_Supporting PS3_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The c.1376C>A variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by aspartic acid at amino acid 459 (p.Ala459Asp). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL. One proband had a family history of disease with reported antithrombin activity level and one proband had a family history of disease but no antithrombin activity level was reported (PS4_Supporting; PMIDs: 8401542, 23809926). This variant is absent from gnomAD v2.1.1, v3.1.2 and v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.756, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). AT activity levels are shown to be reduced (27%) of WT when Ala459Asp was expressed in COS (PMID:23809926), meeting criteria for PS3_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: PP3, PM2_Supporting, PS4_Supporting, PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343772066/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:1
• Conservation: PhyloP100: 7.32

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.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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 rank	MANE	Protein	UniProt
SERPINC1	NM_000488.4	c.1376C>A	p.Ala459Asp	missense_variant	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.1376C>A	p.Ala459Asp	missense_variant	Exon 7 of 7	1	NM_000488.4	ENSP00000356671.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 20, 2024

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1376C>A variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by aspartic acid at amino acid 459 (p.Ala459Asp). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL. One proband had a family history of disease with reported antithrombin activity level and one proband had a family history of disease but no antithrombin activity level was reported (PS4_Supporting; PMIDs: 8401542, 23809926). This variant is absent from gnomAD v2.1.1, v3.1.2 and v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.756, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). AT activity levels are shown to be reduced (27%) of WT when Ala459Asp was expressed in COS (PMID: 23809926), meeting criteria for PS3_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: PP3, PM2_Supporting, PS4_Supporting, PS3_Supporting. -

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
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	.;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0070	.;D
Sift4G	Uncertain	0.037	D;D
Polyphen		1.0	.;D
Vest4		0.75
MutPred		0.78		.;Gain of ubiquitination at K464 (P = 0.0276);
MVP		0.79
MPC		1.4
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.95

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: rs1572084448; hg19: chr1-173873046;