1-173904044-C-T

Position:

• chr1-173904044-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2_Supporting PM1 PS4_Moderate PP3 PP4 PP1

This summary comes from the ClinGen Evidence Repository: The c.1240G>A variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 414 (p.Ala414Thr). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:36764659). This variant has been reported in 4 more probands meeting an antithrombin activity level of < 0.8 IU/mL on repeated independent tests or a family history of disease with reported antithrombin levels (PS4_Moderate, 3.5pts; PMID:25466846, 24684277, 3179438, 28300866). One proband did not meet the full requirements and thus half a point is awarded. The variant has been reported to segregate with hereditary antithrombin deficiency in at least 2 additional affected family members from one family (PP1; PMID:3179438).This variant resides within a residue, Ala414, of SERPINC1 that is defined as a reactive site residue by the ClinGen Thrombosis VCEP (PMID:2615648, PM1). The computational predictor REVEL gives a score of 0.85, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003390 (4/1180010 alleles) in European (non-Finnish) population, which is lower than the ClinGen Thrombosis VCEP threshold (<0.00002) for PM2_Supporting, meeting this criterion (PM2_Supporting).In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PM1, PS4_moderate, PP1, PP3, PP4, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210768/MONDO:0013144/084

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.22

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 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.
• PP4: 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.1240G>A	p.Ala414Thr	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.1240G>A	p.Ala414Thr	missense_variant	7/7	1	NM_000488.4	ENSP00000356671.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Dec 20, 2024	The c.1240G>A variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 414 (p.Ala414Thr). At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:36764659). This variant has been reported in 4 more probands meeting an antithrombin activity level of < 0.8 IU/mL on repeated independent tests or a family history of disease with reported antithrombin levels (PS4_Moderate, 3.5pts; PMID:25466846, 24684277, 3179438, 28300866). One proband did not meet the full requirements and thus half a point is awarded. The variant has been reported to segregate with hereditary antithrombin deficiency in at least 2 additional affected family members from one family (PP1; PMID:3179438). This variant resides within a residue, Ala414, of SERPINC1 that is defined as a reactive site residue by the ClinGen Thrombosis VCEP (PMID:2615648, PM1). The computational predictor REVEL gives a score of 0.85, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000003390 (4/1180010 alleles) in European (non-Finnish) population, which is lower than the ClinGen Thrombosis VCEP threshold (<0.00002) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PM1, PS4_moderate, PP1, PP3, PP4, PM2_supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 23, 2023	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINC1 protein function. ClinVar contains an entry for this variant (Variation ID: 18020). This variant is also known as Ala382>Thr. This missense change has been observed in individual(s) with antithrombin III deficiency (PMID: 2615648, 3179438, 24684277, 25466846, 28300866). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 414 of the SERPINC1 protein (p.Ala414Thr). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 27, 2024

PP1, PP3, PM1, PM2_moderate, PS4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	.;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.7	.;H
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	.;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	.;D
Vest4		0.65
MutPred		0.87		.;Gain of phosphorylation at A414 (P = 0.0213);
MVP		0.93
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.93

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: rs121909557; hg19: chr1-173873182;