chr20-23048087-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:6

Conservation

PhyloP100: -0.384

Publications

80 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=0.0045407116).

BP6

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

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 rank	MANE	Protein	UniProt
THBD	NM_000361.3 link	c.1418C>T	p.Ala473Val	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.1418C>T	p.Ala473Val	missense_variant	Exon 1 of 1	6	NM_000361.3	ENSP00000366307.2		P07204
ENSG00000296483	ENST00000739851.1 link	n.795+2732C>T		intron_variant	Intron 1 of 1

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

GnomAD2 exomes

AF:

0.191

AC:

46637

AN:

243568

AF XY:

0.190

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 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

African (AFR)

AF:

0.0413

AC:

1383

AN:

33460

American (AMR)

AF:

0.179

AC:

7968

AN:

44502

Ashkenazi Jewish (ASJ)

AF:

0.0747

AC:

1945

AN:

26054

East Asian (EAS)

AF:

0.277

AC:

10959

AN:

39630

South Asian (SAS)

AF:

0.178

AC:

15373

AN:

86168

European-Finnish (FIN)

AF:

0.286

AC:

15018

AN:

52438

Middle Eastern (MID)

AF:

0.0593

AC:

342

AN:

5764

European-Non Finnish (NFE)

AF:

0.191

AC:

212140

AN:

1111272

Other (OTH)

AF:

0.171

AC:

10286

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

16674

33348

50023

66697

83371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7462

14924

22386

29848

37310

<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:

0.153

AC:

23310

AN:

152284

Hom.:

2216

Cov.:

AF XY:

0.159

AC XY:

11843

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0497

AC:

2065

AN:

41582

American (AMR)

AF:

0.156

AC:

2383

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0703

AC:

244

AN:

3470

East Asian (EAS)

AF:

0.291

AC:

1504

AN:

5170

South Asian (SAS)

AF:

0.170

AC:

822

AN:

4824

European-Finnish (FIN)

AF:

0.297

AC:

3147

AN:

10606

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.187

AC:

12691

AN:

68008

Other (OTH)

AF:

0.143

AC:

302

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

974

1948

2923

3897

4871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.168

Hom.:

5735

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 20, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23332921, 23520161, 9157575, 29592796, 33103541) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Variant of unknown significance

Uncertain:1

Dec 01, 2004

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

THBD-related disorder

Benign:1

Jan 28, 2024

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 05, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

-0.38

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

Mutation Taster

=99/1

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