rs41348347

Positions:

chr20-23048049-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000361.3(THBD):c.1456G>T(p.Asp486Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,612,354 control chromosomes in the GnomAD database, including 79 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 0.0029 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 69 hom. )

Consequence

THBD
NM_000361.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: -0.842

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=0.002846241).

BP6

Variant 20-23048049-C-A is Benign according to our data. Variant chr20-23048049-C-A is described in ClinVar as [Benign]. Clinvar id is 12714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-23048049-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00288 (439/152378) while in subpopulation AMR AF= 0.023 (352/15310). AF 95% confidence interval is 0.021. There are 10 homozygotes in gnomad4. There are 221 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 439 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THBD	NM_000361.3 link	c.1456G>T	p.Asp486Tyr	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 link	c.1456G>T	p.Asp486Tyr	missense_variant	1/1	6	NM_000361.3	ENSP00000366307.2		P07204

Frequencies

GnomAD3 genomes

AF:

0.00287

AC:

437

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00924

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00838

AC:

2054

AN:

245174

Hom.:

AF XY:

0.00646

AC XY:

861

AN XY:

133248

show subpopulations

Gnomad AFR exome

AF:

0.000515

Gnomad AMR exome

AF:

0.0512

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0114

Gnomad SAS exome

AF:

0.00115

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000227

Gnomad OTH exome

AF:

0.00518

GnomAD4 exome

AF:

0.00193

AC:

2820

AN:

1459976

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

1261

AN XY:

726292

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.0456

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0107

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000139

Gnomad4 OTH exome

AF:

0.00159

GnomAD4 genome

AF:

0.00288

AC:

439

AN:

152378

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

221

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.0230

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00927

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.00563

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00649

AC:

787

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2020	This variant is associated with the following publications: (PMID: 26034596, 7811989, 19625716, 25135378, 20595690, 23332921) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Thrombomodulin-related bleeding disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 01, 2002

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 24, 2019

- -

THBD-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2021

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). -

Kidney disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Atypical hemolytic-uremic syndrome with thrombomodulin anomaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.48

DANN

Benign

0.73

DEOGEN2

Benign

0.24

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.98

REVEL

Benign

0.24

Sift

Benign

0.27

Sift4G

Benign

0.091

Polyphen

0.54

Vest4

0.23

MVP

0.25

ClinPred

0.0034

GERP RS

-5.3

Varity_R

0.053

gMVP

0.56

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