rs1800578

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000361.3(THBD):c.1483C>T(p.Pro495Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,609,724 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00067 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

THBD
NM_000361.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:3O:1

Conservation

PhyloP100: -0.445

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023445576).

BP6

Variant 20-23048022-G-A is Benign according to our data. Variant chr20-23048022-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12720.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=3}. Variant chr20-23048022-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000669 (102/152372) while in subpopulation NFE AF= 0.00129 (88/68038). AF 95% confidence interval is 0.00107. There are 1 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THBD	NM_000361.3 linkuse as main transcript	c.1483C>T	p.Pro495Ser	missense_variant	1/1	ENST00000377103.3	NP_000352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THBD	ENST00000377103.3 linkuse as main transcript	c.1483C>T	p.Pro495Ser	missense_variant	1/1		NM_000361.3	ENSP00000366307	P1

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000493

AC:

117

AN:

237468

Hom.:

AF XY:

0.000433

AC XY:

AN XY:

129422

show subpopulations

Gnomad AFR exome

AF:

0.0000687

Gnomad AMR exome

AF:

0.0000297

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000993

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.000346

GnomAD4 exome

AF:

0.00144

AC:

2101

AN:

1457352

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

992

AN XY:

724712

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.000249

Gnomad4 NFE exome

AF:

0.00177

Gnomad4 OTH exome

AF:

0.00193

GnomAD4 genome

AF:

0.000669

AC:

102

AN:

152372

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000264

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.000691

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000446

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	THBD: BP4, BS1, BS2 -

Atypical hemolytic-uremic syndrome

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Sep 06, 2018	This patient is heterozygous for a known pathogenic variant, c.1483C>T (p.Pro495Ser), in the THBD gene. This variant (dbSNP: rs1800578) is in the ExAC database (http://exac.broadinstitute.org) with an allele frequency of 0.10% (51/50264 alleles) in the European non-Finnish population. It has also been reported in a patient with recurrent atypical hemolytic-uremic syndrome (aHUS) with the first episode at 3 years of age. Other clinical findings were residual renal dysfunction and low serum C3 levels (Delvaeye et al 2009 N Eng J Med 361:345-57). The authors also performed in vitro functional studies which showed the mutant THBD protein did not protect against complement activation. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 13, 2021	- -

Thrombomodulin-related bleeding disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

THBD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2024

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). -

Atypical hemolytic-uremic syndrome with thrombomodulin anomaly

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 23, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

3.6

DANN

Benign

0.90

DEOGEN2

Uncertain

0.54

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.44

M_CAP

Benign

0.064

MetaRNN

Benign

0.023

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.28

Sift

Benign

0.15

Sift4G

Uncertain

0.056

Polyphen

0.068

Vest4

0.17

MVP

0.31

ClinPred

0.015

GERP RS

-0.88

Varity_R

0.050

gMVP

0.58

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over