chr20-23049378-C-T

Position:

chr20-23049378-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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:6O:2

Conservation

PhyloP100: -1.09

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=0.0040130317).

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 id is 12718.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=3}. Variant chr20-23049378-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 383 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBD	NM_000361.3 linkuse as main transcript	c.127G>A	p.Ala43Thr	missense_variant	1/1	ENST00000377103.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBD	ENST00000377103.3 linkuse as main transcript	c.127G>A	p.Ala43Thr	missense_variant	1/1		NM_000361.3	P1

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

GnomAD3 exomes

AF:

0.00200

AC:

432

AN:

215894

Hom.:

AF XY:

0.00199

AC XY:

237

AN XY:

118936

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 SAS exome

AF:

0.000829

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

Gnomad4 AFR exome

AF:

0.000693

Gnomad4 AMR exome

AF:

0.00177

Gnomad4 ASJ exome

AF:

0.0000390

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00112

Gnomad4 FIN exome

AF:

0.000534

Gnomad4 NFE exome

AF:

0.00459

Gnomad4 OTH exome

AF:

0.00342

GnomAD4 genome

AF:

0.00252

AC:

383

AN:

151910

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

169

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.000820

Gnomad4 AMR

AF:

0.00446

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000423

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00400

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00346

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:6Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2019	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 14, 2022	BP4 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Atypical hemolytic-uremic syndrome with thrombomodulin anomaly

Uncertain:1Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
risk factor, no assertion criteria provided	literature only	OMIM	Jul 23, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Feb 25, 2024	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. -

Atypical hemolytic-uremic syndrome

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 07, 2020	- -
risk factor, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Mar 06, 2018	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

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 30, 2021

- -

THBD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2020

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

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

MutationTaster

Benign

1.0

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

Varity_R

0.076

gMVP

0.42

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