1-173914725-C-T

Position:

chr1-173914725-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS4PM1PP1_StrongPP3PP4

This summary comes from the ClinGen Evidence Repository: The c.236G>A (p.Arg79His) variant is reported at an FAF of 0.0002303 and MAF of 0.0003380 (23/68044 alleles) in the non-Finnish European population in gnomAD v3.1.1 meeting BS1 criteria of MAF >0.0002. However, this variant is an established founder variant known as AT Padua I making it ineligible for the BS1 rule application. It has a REVEL score of 0.702, and meets PP3. At least 23 individuals with AT deficiency meeting the SERPINC1 phenotype criteria (other cases are reported but do not meet criteria) are reported in the literature meeting PS4_Very Strong and PP4. Additionally, 9 meioses have been reported across 16 families meeting PP1_Strong. In summary, this variant reaches a classification of pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Strong, PM1, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210758/MONDO:0013144/084

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

SERPINC1
NM_000488.4 missense

Scores

3

13

3

Clinical Significance

Pathogenic reviewed by expert panel P:10U:2B:1

Conservation

PhyloP100: 5.83

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:

SERPINC1 (HGNC:):

SERPINC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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.

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.236G>A	p.Arg79His	missense_variant	2/7	ENST00000367698.4	NP_000479.1	P01008A0A024R944

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINC1	ENST00000367698.4 linkuse as main transcript	c.236G>A	p.Arg79His	missense_variant	2/7	1	NM_000488.4	ENSP00000356671.3		P01008
SERPINC1	ENST00000494024.1 linkuse as main transcript	n.462G>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

27

AN:

152228

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000954

AC:

24

AN:

251464

Hom.:

0

AF XY:

0.0000589

AC XY:

8

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000231

AC:

337

AN:

1461882

Hom.:

0

Cov.:

31

AF XY:

0.000246

AC XY:

179

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000281

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000177

AC:

27

AN:

152346

Hom.:

0

Cov.:

32

AF XY:

0.000161

AC XY:

12

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000361

Hom.:

0

Bravo

AF:

0.000208

ESP6500AA

AF:

0.000454

AC:

2

ESP6500EA

AF:

0.000233

AC:

2

ExAC

AF:

0.0000494

AC:

6

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Uncertain:2Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary antithrombin deficiency

Pathogenic:7Uncertain:2Benign:1

Pathogenic, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Sep 21, 2023	The c.236G>A (p.Arg79His) variant is reported at an FAF of 0.0002303 and MAF of 0.0003380 (23/68044 alleles) in the non-Finnish European population in gnomAD v3.1.1 meeting BS1 criteria of MAF >0.0002. However, this variant is an established founder variant known as AT Padua I making it ineligible for the BS1 rule application. It has a REVEL score of 0.702, and meets PP3. At least 23 individuals with AT deficiency meeting the SERPINC1 phenotype criteria (other cases are reported but do not meet criteria) are reported in the literature meeting PS4_Very Strong and PP4. Additionally, 9 meioses have been reported across 16 families meeting PP1_Strong. In summary, this variant reaches a classification of pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Strong, PM1, PP3, PP4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1994	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 03, 2017	The SERPINC1 c.236G>A (p.Arg79His) missense variant has been identified in a heterozygous state in five patients with antithrombin-III (AT) deficiency (Orlando et al. 2015). Gindele et al. (2016) also reported this variant in 6.7% of patients with type II heparin binding site deficiency (HBS). In the Orlando et al. (2015) study, two patients each also had arterial events and venous thrombotic events, respectively. However, another study indicated that endogenous thrombin potential was not increased in carriers of the p.Arg79His variant, thereby suggesting that this variant is associated with a low risk of venous thromboembolism (Alhenc-Gelas et al. 2010). In addition, using multiple commercially available methods, AT activity was measured in the five patients from the Orlando et al. (2015) study and activity was decreased in some cases, but some of these methods did not show decreased activity. Another variant at this amino acid position, p.Arg79Cys, has also been observed in patients (Orlando et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg79His variant is classified as a variant of unknown significance but suspicious for pathogenicity for antithrombin-III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 11, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Uncertain significance, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 10, 2024	Criteria applied: PS4_VSTR,PM1,PM5,PP3,PP1_STR -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 79 of the SERPINC1 protein (p.Arg79His). This variant is present in population databases (rs121909552, gnomAD 0.02%). This missense change has been observed in individuals with antithrombin deficiency (PMID: 2363123, 2615648, 3567355, 7981186, 21264449, 25837307, 26748602, 28607330, 29153735, 31885188, 35626216). This variant is also known as R47H, Arg47His, AT Padua I, AT Rouen I, or AT III Bligny. ClinVar contains an entry for this variant (Variation ID: 18014). 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 not expected to disrupt SERPINC1 protein function with a negative predictive value of 95%. This variant disrupts the p.Arg79 (also known as p.Arg47) amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 6582486, 21325262, 24162787, 28300866). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 07, 2024	PP1_strong, PP5, PM1, PM2_moderate, PM5, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	SERPINC1: PS1, PM1, PP1, PP4, PS3:Supporting, PS4:Supporting -

SERPINC1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2024

The SERPINC1 c.236G>A variant is predicted to result in the amino acid substitution p.Arg79His. This variant is a known causative variant for antithrombin deficiency and has been documented in the literature under many different names, including p.Arg47His and AT Rouen (Owen et al. 1987. PubMed ID: 3567355; Emmerich et al. 1994. PubMed ID: 7981186; Yoo et al. 2011. PubMed ID: 21325262). Functional studies have shown that this variant leads to partial misfolding (Emmerich et al. 1994. PubMed ID: 7981186), and a shorten thrombin half-life (Reda et al. 2021. PubMed ID: 33672736). This variant is reported in 0.018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.13

D

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

26

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

.;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

D

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.086

D

MetaRNN

Benign

0.38

T;T

MetaSVM

Uncertain

0.086

D

MutationAssessor

Uncertain

2.2

.;M

PrimateAI

Uncertain

0.69

T

PROVEAN

Benign

-1.5

.;N

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0040

.;D

Sift4G

Uncertain

0.017

D;D

Polyphen

0.98

.;D

Vest4

0.67

MVP

0.94

MPC

0.79

ClinPred

0.19

T

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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: rs121909552; hg19: chr1-173883863; COSMIC: COSV62930719; COSMIC: COSV62930719;