rs1800576

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000361.3(THBD):c.127G>A(p.Ala43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,598,276 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A43A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 12 hom. )

Consequence

THBD
NM_000361.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7O:2

Conservation

PhyloP100: -1.09

Publications

30 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040130317).

BP6

Variant 20-23049378-C-T is Benign according to our data. Variant chr20-23049378-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12718.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00252 (383/151910) while in subpopulation AMR AF = 0.00446 (68/15254). AF 95% confidence interval is 0.00361. There are 1 homozygotes in GnomAd4. There are 169 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THBD	NM_000361.3 link	c.127G>A	p.Ala43Thr	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.127G>A	p.Ala43Thr	missense_variant	Exon 1 of 1	6	NM_000361.3	ENSP00000366307.2		P07204
ENSG00000296483	ENST00000739851.1 link	n.795+1441G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00252

AC:

383

AN:

151782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000822

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00446

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000424

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00400

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00200

AC:

432

AN:

215894

AF XY:

0.00199

show subpopulations

Gnomad AFR exome

AF:

0.00108

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000328

Gnomad NFE exome

AF:

0.00357

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.00381

AC:

5506

AN:

1446366

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

2709

AN XY:

718436

show subpopulations

African (AFR)

AF:

0.000693

AC:

AN:

33176

American (AMR)

AF:

0.00177

AC:

AN:

43422

Ashkenazi Jewish (ASJ)

AF:

0.0000390

AC:

AN:

25672

East Asian (EAS)

AF:

0.00

AC:

AN:

38914

South Asian (SAS)

AF:

0.00112

AC:

AN:

84092

European-Finnish (FIN)

AF:

0.000534

AC:

AN:

50564

Middle Eastern (MID)

AF:

0.000352

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00459

AC:

5078

AN:

1105194

Other (OTH)

AF:

0.00342

AC:

204

AN:

59644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

341

681

1022

1362

1703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.00252

AC:

383

AN:

151910

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

169

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.000820

AC:

AN:

41470

American (AMR)

AF:

0.00446

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.000423

AC:

AN:

4724

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00400

AC:

272

AN:

67948

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00328

Hom.:

Bravo

AF:

0.00278

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00186

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00176

AC:

210

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Nov 19, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19625716, 28752844, 23332921, 24853860, 9198186, 25079699, 20595690) -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

THBD: BS2 -

Atypical hemolytic-uremic syndrome with thrombomodulin anomaly

Uncertain:1Benign:1Other: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. -

Feb 25, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The THBD c.127G>A (p.Ala43Thr) variant has been observed in multiple individuals with atypical hemolytic uremic syndrome (aHUS) (Gaut JP et al., PMID: 28752844; Vaught AJ et al., PMID: 29563339; Fremeaux-Bacchi V et al., PMID: 23307876). However, this variant has also been observed in some apparently unaffected relatives, suggesting incomplete penetrance or variable expressivity of the phenotype (Delvaeye M et al., PMID: 19625716). This variant is observed on 502/247,256 alleles in the general population (gnomAD v2.1.1). Computational predictors suggest that the variant does not impact THBD function, however, functional studies show that this alanine to threonine amino acid change results in decreased capacity to inactivate C3b (Delvaeye M et al., PMID: 19625716). Due to conflicting information and based on the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the THBD c.127G>A (p.Ala43Thr) variant is uncertain at this time. -

Jul 23, 2009

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Atypical hemolytic-uremic syndrome

Benign:1Other:1

Jul 07, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:clinical testing

This patient is heterozygous for a variant, c.127G>A (p.Ala43Thr), in the THBD gene. This variant (dbSNP: rs1800576) has been previously reported in the Exome Aggregation Consortium (ExAC) database (http://exac.broadinstitute.org/) with a minor allele frequency of 0.34% (172 out of 50152 alleles). This variant has also been previously reported in the heterozygote state in a man with recurrent atypical haemolytic uremic syndrome (aHUS) since infancy, with chronic renal failure and decreased serum C3 (Delvaeye et al 2009 N Engl J Med 361:345-357). The patient had affected and unaffected family members who were also heterozygote for this variant. In vitro functional studies by the same group showed the mutant p.Ala43Thr did not protect cultured cells against complement activation suggesting that this variant affects function. -

not specified

Benign:1

Aug 30, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

THBD-related disorder

Benign:1

Mar 12, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.0

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.15

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

-1.1

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.39

REVEL

Benign

0.014

Sift

Benign

0.53

Sift4G

Benign

0.57

Polyphen

0.022

Vest4

0.051

MVP

0.15

ClinPred

0.0014

GERP RS

1.6

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.076

gMVP

0.42

Mutation Taster

=93/7

polymorphism

(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