chr1-173903973-G-C

Position:

chr1-173903973-G-C

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PS4PP1_StrongPP3

This summary comes from the ClinGen Evidence Repository: The c.1311C>G (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of asparagine by lysine at amino acid 437 (p.Asn437Lys). The computational predictor REVEL gives a score of 0.683, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. The variant has been reported in at least 8 probands with AT deficiency in the literature (7.5 points applied PMID 28300866; PMID 24684277; PMID 12755798; PMID 1469094). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in 7 affected family meioses from 4 families (PP1_strong; PMID:1469094; PMID:12755798; PMID:28300866). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_Strong, PS4, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343772391/MONDO:0013144/084

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SERPINC1
NM_000488.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:2

Conservation

PhyloP100: 2.48

Variant links:

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]

SERPINC1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 9 ACMG points.

PS4

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 linkuse as main transcript	c.1311C>G	p.Asn437Lys	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 linkuse as main transcript	c.1311C>G	p.Asn437Lys	missense_variant	7/7	1	NM_000488.4	ENSP00000356671	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251362

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461580

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary antithrombin deficiency

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 437 of the SERPINC1 protein (p.Asn437Lys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with antithrombin III deficiency (PMID: 1469094, 1796410, 12755798, 33725558). It has also been observed to segregate with disease in related individuals. This variant is also known as Asn405Lys. 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Feb 19, 2024	The c.1311C>G (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of asparagine by lysine at amino acid 437 (p.Asn437Lys). The computational predictor REVEL gives a score of 0.683, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. The variant has been reported in at least 8 probands with AT deficiency in the literature (7.5 points applied PMID 28300866; PMID 24684277; PMID 12755798; PMID 1469094). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in 7 affected family meioses from 4 families (PP1_strong; PMID: 1469094; PMID: 12755798; PMID: 28300866). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_Strong, PS4, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

.;D

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Pathogenic

3.2

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.6

.;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0060

.;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

.;D

Vest4

0.62

MutPred

0.92

.;Gain of methylation at N437 (P = 0.0097);

MVP

0.92

MPC

1.2

ClinPred

0.98

GERP RS

2.8

Varity_R

0.93

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over