rs41348347

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D486E) has been classified as Uncertain significance.

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:8

Conservation

PhyloP100: -0.842

Publications

32 publications found

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 Gene-Disease associations (from GenCC):

atypical hemolytic-uremic syndrome with thrombomodulin anomaly
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
thrombomodulin-related bleeding disorder
Inheritance: AR, AD, Unknown Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

THBD links:

ENSG00000296483 (HGNC:):

ENSG00000296483 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 12714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THBD	NM_000361.3 link	c.1456G>T	p.Asp486Tyr	missense_variant	Exon 1 of 1	ENST00000377103.3	NP_000352.1	P07204

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THBD	ENST00000377103.3 link	c.1456G>T	p.Asp486Tyr	missense_variant	Exon 1 of 1	6	NM_000361.3	ENSP00000366307.2		P07204
ENSG00000296483	ENST00000739851.1 link	n.795+2770G>T		intron_variant	Intron 1 of 1

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

GnomAD2 exomes

AF:

0.00838

AC:

2054

AN:

245174

AF XY:

0.00646

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 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

African (AFR)

AF:

0.000359

AC:

AN:

33466

American (AMR)

AF:

0.0456

AC:

2028

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.0107

AC:

423

AN:

39632

South Asian (SAS)

AF:

0.00122

AC:

105

AN:

86100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52770

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000139

AC:

155

AN:

1111394

Other (OTH)

AF:

0.00159

AC:

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

225

451

676

902

1127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.00288

AC:

439

AN:

152378

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

221

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41596

American (AMR)

AF:

0.0230

AC:

352

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00927

AC:

AN:

5180

South Asian (SAS)

AF:

0.00103

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68038

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00150

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 27, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26034596, 7811989, 19625716, 25135378, 20595690, 23332921) -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

THBD: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Thrombomodulin-related bleeding disorder

Uncertain:1

Aug 01, 2002

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:1

Oct 24, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kidney disorder

Benign:1

Mar 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

THBD-related disorder

Benign:1

Jun 05, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

-0.84

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over