chr1-173903969-G-T

Position:

chr1-173903969-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4PP1_ModeratePS3_SupportingPP3PP4PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1315C>A (p.Pro439Thr) variant is reported at an MAF of (FAF not available), 1/68048 alleles in the non-Finnish European population in gnomAD v3.1.1 and meets criteria for PM2_Supporting (threshold <0.00002). It has a REVEL score of 0.88 and meets criteria for PP3. Several probands can be counted across the literature, who meet phenotype criteria for AT deficiency with a mix of repeat sampling, meeting PP4 and PS4. Four segregations are counted across two families meeting criteria for PP1_Moderate. Expression of mutant AT, 439Thr-AT, in HEK293 cells described in PMID:18480576 revealed decrease in AT secretion, meeting criteria for PS3_Supporting. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4, PP1_Moderate, PP3, PP4, PM2_Supporting, PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343772370/MONDO:0013144/084

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SERPINC1
NM_000488.4 missense

Scores

14

4

1

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 9.14

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 10 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.

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 linkuse as main transcript	c.1315C>A	p.Pro439Thr	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.1315C>A	p.Pro439Thr	missense_variant	7/7	1	NM_000488.4	ENSP00000356671	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152198

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461810

Hom.:

0

Cov.:

31

AF XY:

0.00000138

AC XY:

1

AN XY:

727220

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152198

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary antithrombin deficiency

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Sep 21, 2023	The c.1315C>A (p.Pro439Thr) variant is reported at an MAF of (FAF not available), 1/68048 alleles in the non-Finnish European population in gnomAD v3.1.1 and meets criteria for PM2_Supporting (threshold <0.00002). It has a REVEL score of 0.88 and meets criteria for PP3. Several probands can be counted across the literature, who meet phenotype criteria for AT deficiency with a mix of repeat sampling, meeting PP4 and PS4. Four segregations are counted across two families meeting criteria for PP1_Moderate. Expression of mutant AT, 439Thr-AT, in HEK293 cells described in PMID: 18480576 revealed decrease in AT secretion, meeting criteria for PS3_Supporting. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4, PP1_Moderate, PP3, PP4, PM2_Supporting, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2023	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 439 of the SERPINC1 protein (p.Pro439Thr). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro439 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16705712, 23910795, 28300866; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 18480576). 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) performed at Invitae indicates that this missense variant is expected to disrupt SERPINC1 protein function. ClinVar contains an entry for this variant (Variation ID: 627228). This variant is also known as P407T. This missense change has been observed in individual(s) with antithrombin III deficiency (PMID: 1469094, 24814625, 28229161, 29153735, 31030036, 31064749). -

Abnormal thrombosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.56

D

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

29

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

.;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.17

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.2

D

MutationAssessor

Pathogenic

3.9

.;H

MutationTaster

Benign

1.0

D

PrimateAI

Uncertain

0.66

T

PROVEAN

Pathogenic

-7.3

.;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.93

MutPred

0.96

.;Gain of MoRF binding (P = 0.0468);

MVP

0.99

MPC

1.2

ClinPred

1.0

D

GERP RS

5.7

Varity_R

0.96

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

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

Other links and lift over

dbSNP: rs1487411568; hg19: chr1-173873107; COSMIC: COSV62930399; COSMIC: COSV62930399;