rs1800576

Positions:

• chr20-23049378-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6 O:2
• Conservation: PhyloP100: -1.09

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]

ACMG classification

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	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	c.127G>A	p.Ala43Thr	missense_variant	1/1		NM_000361.3	P1

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 383 AN: 151782 Hom.: 1 Cov.: 33

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.: 0 AF XY: 0.00199 AC XY: 237 AN XY: 118936

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.: 12 Cov.: 34 AF XY: 0.00377 AC XY: 2709 AN XY: 718436

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.: 1 Cov.: 33 AF XY: 0.00228 AC XY: 169 AN XY: 74278

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.: 3

Bravo AF: 0.00278

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00186 AC: 8

ESP6500EA AF: 0.00453 AC: 38

ExAC AF: 0.00176 AC: 210

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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:1 Benign:1 Other: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:1 Other: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	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.0
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.014
Sift	Benign	0.53	T
Sift4G	Benign	0.57	T
Polyphen		0.022	B
Vest4		0.051
MVP		0.15
ClinPred		0.0014	T
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

Other links and lift over

dbSNP: rs1800576; hg19: chr20-23030015; COSMIC: COSV101001938;