Genetic Variant THBD:p.Ala473Asp (chr20-23048087-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000361.3(THBD):c.1418C>A(p.Ala473Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A473V) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

THBD
NM_000361.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06777719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THBD	NM_000361.3 link	c.1418C>A	p.Ala473Asp	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>A	p.Ala473Asp	missense_variant	Exon 1 of 1	6	NM_000361.3	ENSP00000366307.2		P07204
ENSG00000296483	ENST00000739851.1 link	n.795+2732C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

243568

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459558

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726030

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111292

Other (OTH)

AF:

0.0000332

AC:

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.9

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.29

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.24

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.068

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

PhyloP100

-0.38

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.0

REVEL

Benign

0.14

Sift

Benign

0.42

Sift4G

Benign

0.18

Polyphen

0.0010

Vest4

0.072

MutPred

0.42

Gain of disorder (P = 0.057);

MVP

0.17

ClinPred

0.067

GERP RS

-1.3

Varity_R

0.34

gMVP

0.82

Mutation Taster

=95/5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over