rs121909548

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_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 Likely 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:2B: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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000488.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-173904038-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINC1	NM_000488.4 linkuse as main transcript	c.1246G>T	p.Ala416Ser	missense_variant	7/7	ENST00000367698.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINC1	ENST00000367698.4 linkuse as main transcript	c.1246G>T	p.Ala416Ser	missense_variant	7/7	1	NM_000488.4	P1

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

GnomAD3 exomes

AF:

0.000887

AC:

223

AN:

251358

Hom.:

AF XY:

0.000832

AC XY:

113

AN XY:

135860

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 SAS exome

AF:

0.0000653

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

Gnomad4 AMR exome

AF:

0.00163

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00181

Gnomad4 OTH exome

AF:

0.00146

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

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00168

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00134

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:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary antithrombin deficiency

Pathogenic:3Uncertain:1Benign:1

Likely pathogenic, no assertion criteria provided	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 22, 1991	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 28, 2021	ACMG classification criteria: PS3 supporting, PS4 strong, PM3 moderate -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2022	PP1_strong, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -

Thrombocytopenia;C1458140:Abnormal bleeding

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

MutationTaster

Benign

1.0

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

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