rs1042579

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000361.3(THBD):c.1418C>T(p.Ala473Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,611,792 control chromosomes in the GnomAD database, including 29,920 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2216 hom., cov: 34)

Exomes 𝑓: 0.19 ( 27704 hom. )

Consequence

THBD
NM_000361.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:5

Conservation

PhyloP100: -0.384

Variant links:

Genes affected

THBD (HGNC:11784): (thrombomodulin) The protein encoded by this intronless gene is an endothelial-specific type I membrane receptor that binds thrombin. This binding results in the activation of protein C, which degrades clotting factors Va and VIIIa and reduces the amount of thrombin generated. Mutations in this gene are a cause of thromboembolic disease, also known as inherited thrombophilia. [provided by RefSeq, Jul 2008]

THBD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045407116).

BP6

Variant 20-23048087-G-A is Benign according to our data. Variant chr20-23048087-G-A is described in ClinVar as [Benign]. Clinvar id is 337883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-23048087-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBD	NM_000361.3 linkuse as main transcript	c.1418C>T	p.Ala473Val	missense_variant	1/1	ENST00000377103.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBD	ENST00000377103.3 linkuse as main transcript	c.1418C>T	p.Ala473Val	missense_variant	1/1		NM_000361.3	P1

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23314

AN:

152166

Hom.:

2218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0499

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.156

Gnomad ASJ

AF:

0.0703

Gnomad EAS

AF:

0.289

Gnomad SAS

AF:

0.170

Gnomad FIN

AF:

0.297

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.187

Gnomad OTH

AF:

0.144

GnomAD3 exomes

AF:

0.191

AC:

46637

AN:

243568

Hom.:

5001

AF XY:

0.190

AC XY:

25221

AN XY:

132670

show subpopulations

Gnomad AFR exome

AF:

0.0500

Gnomad AMR exome

AF:

0.187

Gnomad ASJ exome

AF:

0.0748

Gnomad EAS exome

AF:

0.293

Gnomad SAS exome

AF:

0.180

Gnomad FIN exome

AF:

0.292

Gnomad NFE exome

AF:

0.192

Gnomad OTH exome

AF:

0.167

GnomAD4 exome

AF:

0.189

AC:

275414

AN:

1459508

Hom.:

27704

Cov.:

AF XY:

0.188

AC XY:

136145

AN XY:

726002

show subpopulations

Gnomad4 AFR exome

AF:

0.0413

Gnomad4 AMR exome

AF:

0.179

Gnomad4 ASJ exome

AF:

0.0747

Gnomad4 EAS exome

AF:

0.277

Gnomad4 SAS exome

AF:

0.178

Gnomad4 FIN exome

AF:

0.286

Gnomad4 NFE exome

AF:

0.191

Gnomad4 OTH exome

AF:

0.171

GnomAD4 genome

AF:

0.153

AC:

23310

AN:

152284

Hom.:

2216

Cov.:

AF XY:

0.159

AC XY:

11843

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0497

Gnomad4 AMR

AF:

0.156

Gnomad4 ASJ

AF:

0.0703

Gnomad4 EAS

AF:

0.291

Gnomad4 SAS

AF:

0.170

Gnomad4 FIN

AF:

0.297

Gnomad4 NFE

AF:

0.187

Gnomad4 OTH

AF:

0.143

Alfa

AF:

0.169

Hom.:

3854

Bravo

AF:

0.138

TwinsUK

AF:

0.188

AC:

697

ALSPAC

AF:

0.205

AC:

789

ESP6500AA

AF:

0.0572

AC:

252

ESP6500EA

AF:

0.179

AC:

1541

ExAC

AF:

0.186

AC:

22579

Asia WGS

AF:

0.212

AC:

734

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2020	This variant is associated with the following publications: (PMID: 23332921, 23520161, 9157575, 29592796, 33103541) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Variant of unknown significance

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Dec 01, 2004

- -

THBD-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Atypical hemolytic-uremic syndrome with thrombomodulin anomaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

Cadd

Benign

5.1

Dann

Benign

0.84

DEOGEN2

Benign

0.32

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

REVEL

Benign

0.17

Sift

Benign

0.40

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.015

ClinPred

0.0017

GERP RS

-1.3

Varity_R

0.15

gMVP

0.69

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