rs121909548

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM5PP2BP4_Moderate

The NM_000488.4(SERPINC1):c.1246G>T(p.Ala416Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,228 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A416P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 1 hom. )

Consequence

SERPINC1
NM_000488.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3B:2

Conservation

PhyloP100: 7.22

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000488.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-173904038-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 18007.Status of the report is reviewed_by_expert_panel, 3 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 1.3587 (below the threshold of 3.09). Trascript score misZ: 2.7609 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary antithrombin deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.2164593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINC1	NM_000488.4 link	c.1246G>T	p.Ala416Ser	missense_variant	Exon 7 of 7	ENST00000367698.4	NP_000479.1	P01008A0A024R944

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINC1	ENST00000367698.4 link	c.1246G>T	p.Ala416Ser	missense_variant	Exon 7 of 7	1	NM_000488.4	ENSP00000356671.3		P01008

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000887

AC:

223

AN:

251358

AF XY:

0.000832

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00140

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00149

AC:

2185

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1009

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00163

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39698

Gnomad4 SAS exome

AF:

0.0000232

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.0000374

AC:

AN:

53414

Gnomad4 NFE exome

AF:

0.00181

AC:

2013

AN:

1112006

Gnomad4 Remaining exome

AF:

0.00146

AC:

AN:

60396

Heterozygous variant carriers

111

222

332

443

554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00109

AC:

166

AN:

152350

Hom.:

Cov.:

AF XY:

0.000899

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000313

AC:

0.000312665

AN:

0.000312665

Gnomad4 AMR

AF:

0.00242

AC:

0.00241704

AN:

0.00241704

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.0000941

AC:

0.0000941265

AN:

0.0000941265

Gnomad4 NFE

AF:

0.00168

AC:

0.00167563

AN:

0.00167563

Gnomad4 OTH

AF:

0.000473

AC:

0.00047259

AN:

0.00047259

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00144

Hom.:

Bravo

AF:

0.00120

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000717

AC:

EpiCase

AF:

0.00169

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary antithrombin deficiency

Pathogenic:3Uncertain:2Benign:1

Jul 22, 1991

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Aug 29, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 28, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM3 moderate -

not provided

Pathogenic:2

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 10, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PS3, PS4 -

Thrombocytopenia;C1458140:Abnormal bleeding

Uncertain:1

May 01, 2020

Birmingham Platelet Group; University of Birmingham

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.22

T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.3

.;M

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.6

.;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.019

D;D

Polyphen

1.0

.;D

Vest4

0.59

MVP

0.86

MPC

1.1

ClinPred

0.15

GERP RS

5.7

Varity_R

0.85

gMVP

0.84

Mutation Taster

=37/63

disease causing

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