rs1800579

Positions:

chr20-23048003-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000361.3(THBD):c.1502C>T(p.Pro501Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00268 in 1,608,780 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 9 hom. )

Consequence

THBD
NM_000361.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6

Conservation

PhyloP100: 4.11

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056052804).

BP6

Variant 20-23048003-G-A is Benign according to our data. Variant chr20-23048003-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 337882.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00193 (294/152358) while in subpopulation NFE AF= 0.00301 (205/68028). AF 95% confidence interval is 0.00268. There are 0 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 294 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THBD	NM_000361.3 linkuse as main transcript	c.1502C>T	p.Pro501Leu	missense_variant	1/1	ENST00000377103.3	NP_000352.1	P07204

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THBD	ENST00000377103.3 linkuse as main transcript	c.1502C>T	p.Pro501Leu	missense_variant	1/1	6	NM_000361.3	ENSP00000366307.2		P07204

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

294

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00301

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00180

AC:

422

AN:

234646

Hom.:

AF XY:

0.00184

AC XY:

236

AN XY:

127946

show subpopulations

Gnomad AFR exome

AF:

0.000283

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00187

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000674

Gnomad FIN exome

AF:

0.00105

Gnomad NFE exome

AF:

0.00300

Gnomad OTH exome

AF:

0.00191

GnomAD4 exome

AF:

0.00275

AC:

4010

AN:

1456422

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

1996

AN XY:

724188

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.00174

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000666

Gnomad4 FIN exome

AF:

0.00132

Gnomad4 NFE exome

AF:

0.00332

Gnomad4 OTH exome

AF:

0.00170

GnomAD4 genome

AF:

0.00193

AC:

294

AN:

152358

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00301

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00286

Hom.:

Bravo

AF:

0.00201

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00292

AC:

ExAC

AF:

0.00178

AC:

215

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 30, 2022	PS3_moderate -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	THBD: BP4, BS1 -

Thrombomodulin-related bleeding disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

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

- -

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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 06, 2024

- -

THBD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2023

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.60

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.26

Sift

Uncertain

0.012

Sift4G

Uncertain

0.021

Polyphen

0.67

Vest4

0.28

MVP

0.52

ClinPred

0.034

GERP RS

4.2

Varity_R

0.13

gMVP

0.71

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