1-173903968-G-A

Position:

• chr1-173903968-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP1_Moderate PM5 PP3 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1316C>T (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 439 (p.Pro439Leu). This variant has been reported in one proband meeting the phenotypic criteria of an antithrombin activity level of < 0.8 IU/mL and a positive family history. (PS4_Supporting; PMIDs: 6877092, 3191114). 12 segregations are counted in the Utah family where 13 members are identified as AT-deficient. 11 individuals showed electrophoretically abnormal AT; 2 individuals are obligate carriers. PMID:3191114 performed sequence analysis on this family. Based on RFLP analysis in this paper, 12 segregations may be counted. However, criteria for PP1_Strong is not met as segregations across >1 family is required (PP1_Moderate; PMID:2983542, 3191114). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.952, 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 likely pathogenic for autosomal dominant antithrombin III deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PM5, PP3, PM2, PS4. (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/CA210764/MONDO:0013144/084

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P: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 Likely_pathogenic. Variant got 7 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.
• PP1: 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.1316C>T	p.Pro439Leu	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.1316C>T	p.Pro439Leu	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: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 09, 1988	- -
Likely pathogenic, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Jan 25, 2024	The c.1316C>T (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 439 (p.Pro439Leu). This variant has been reported in one proband meeting the phenotypic criteria of an antithrombin activity level of < 0.8 IU/mL and a positive family history. (PS4_Supporting; PMIDs: 6877092, 3191114). 12 segregations are counted in the Utah family where 13 members are identified as AT-deficient. 11 individuals showed electrophoretically abnormal AT; 2 individuals are obligate carriers. PMID: 3191114 performed sequence analysis on this family. Based on RFLP analysis in this paper, 12 segregations may be counted. However, criteria for PP1_Strong is not met as segregations across >1 family is required (PP1_Moderate; PMID:2983542, 3191114). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.952, 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 likely pathogenic for autosomal dominant antithrombin III deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PM5, PP3, PM2, PS4. (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	0.78
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	.;H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-9.1	.;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.98
MutPred		0.96		.;Gain of MoRF binding (P = 0.0506);
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
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: rs121909555; hg19: chr1-173873106;