rs1800577

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000361.3(THBD):c.236G>C(p.Gly79Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,551,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G79G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

THBD
NM_000361.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.0980

Publications

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

THBD links:

ENSG00000296483 (HGNC:):

ENSG00000296483 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07544395).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000361.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBD	NM_000361.3	MANE Select	c.236G>C	p.Gly79Ala	missense	Exon 1 of 1	NP_000352.1	P07204

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBD	ENST00000377103.3	TSL:6 MANE Select	c.236G>C	p.Gly79Ala	missense	Exon 1 of 1	ENSP00000366307.2	P07204
	ENSG00000296483	ENST00000739851.1		n.795+1550G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000136

AC:

AN:

146520

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000425

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000175

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000114

AC:

AN:

1398858

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

690802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31488

American (AMR)

AF:

0.0000288

AC:

AN:

34686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25034

East Asian (EAS)

AF:

0.00

AC:

AN:

36382

South Asian (SAS)

AF:

0.00

AC:

AN:

78984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46714

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4732

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

1082814

Other (OTH)

AF:

0.0000172

AC:

AN:

58024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.597

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41554

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000276

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Atypical hemolytic-uremic syndrome with thrombomodulin anomaly;C3280976:Thrombomodulin-related bleeding disorder (1)

Thrombomodulin-related bleeding disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.39

CADD

Benign

9.3

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.098

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.43

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.075

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.6

PhyloP100

0.098

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.86

REVEL

Benign

0.26

Sift

Benign

0.82

Sift4G

Benign

1.0

Polyphen

0.020

Vest4

0.14

MutPred

0.15

Gain of MoRF binding (P = 0.1634)

MVP

0.36

ClinPred

0.041

GERP RS

3.4

PromoterAI

0.0096

Neutral

(source)

Varity_R

0.076

gMVP

0.27

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over