rs121909571

Positions:

chr1-173910861-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4PP1_StrongPP3PP4PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000488.4(SERPINC1):c.655A>G (p.Asn219Asp) missense variant is reported at a Popmax FAF of 0.00000488 (non-Finnish European) in gnomAD v3.1.2 and a frequency of 0.000008792 (1/113744) in gnomAD v2.1.1, meeting criteria for PM2_Supporting. It has a REVEL score of 0.898 (PP3 is >0.6). One proband from PMID:28300866 (family of four affected individuals), 2 probands from PMID:15630491, 1 proband from PMID:7989582, and 1 proband from PMID:7795154 meet phenotype criteria for PS4, PP4 and PP1_Strong. Of note, PMID:30005274 reports that the Asn219Asp variant associated with Type II RS is hardly detected by the different anti-FXa or anti-FIIa assay methods. 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_Strong, PP3, PP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210798/MONDO:0013144/084

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

SERPINC1
NM_000488.4 missense

Scores

11

6

2

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 7.64

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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.

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.655A>G	p.Asn219Asp	missense_variant	4/7	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.655A>G	p.Asn219Asp	missense_variant	4/7	1	NM_000488.4	ENSP00000356671	P1
SERPINC1	ENST00000487183.1 linkuse as main transcript	n.330-24A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152160

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251466

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

58

AN:

1461884

Hom.:

0

Cov.:

32

AF XY:

0.0000454

AC XY:

33

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

2

AN:

152160

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74332

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary antithrombin deficiency

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 10, 2020	PM2, PM5, PS3, PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1994	- -
Pathogenic, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Sep 21, 2023	The NM_000488.4(SERPINC1):c.655A>G (p.Asn219Asp) missense variant is reported at a Popmax FAF of 0.00000488 (non-Finnish European) in gnomAD v3.1.2 and a frequency of 0.000008792 (1/113744) in gnomAD v2.1.1, meeting criteria for PM2_Supporting. It has a REVEL score of 0.898 (PP3 is >0.6). One proband from PMID: 28300866 (family of four affected individuals), 2 probands from PMID: 15630491, 1 proband from PMID: 7989582, and 1 proband from PMID: 7795154 meet phenotype criteria for PS4, PP4 and PP1_Strong. Of note, PMID: 30005274 reports that the Asn219Asp variant associated with Type II RS is hardly detected by the different anti-FXa or anti-FIIa assay methods. 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_Strong, PP3, PP4, PM2_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Oct 01, 2017	[ACMG/AMP: PM2, PM5, PS4_Moderate, PP2, PP3] This alteration is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.20

D

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

25

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Benign

0.83

T

M_CAP

Uncertain

0.23

D

MetaRNN

Pathogenic

0.99

D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

3.9

H

MutationTaster

Benign

1.0

A

PrimateAI

Uncertain

0.60

T

PROVEAN

Pathogenic

-4.6

D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0040

D

Sift4G

Uncertain

0.010

D

Polyphen

1.0

D

Vest4

0.99

MutPred

0.97

Loss of MoRF binding (P = 0.05);

MVP

0.93

MPC

1.2

ClinPred

1.0

D

GERP RS

5.7

Varity_R

0.93

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: rs121909571; hg19: chr1-173879999;