rs1800578

Positions:

• chr20-23048022-G-A
• chr20-23048022-G-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.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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:3 O:1
• Conservation: PhyloP100: -0.445

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=0.023445576).
• 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=2, 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	UniProt
THBD	NM_000361.3	c.1483C>T	p.Pro495Ser	missense_variant	1/1	ENST00000377103.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152252 Hom.: 1 Cov.: 33

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.: 0 AF XY: 0.000433 AC XY: 56 AN XY: 129422

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.: 2 Cov.: 30 AF XY: 0.00137 AC XY: 992 AN XY: 724712

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.: 1 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74512

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.: 0

Bravo AF: 0.000691

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000446 AC: 54

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

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

Atypical hemolytic-uremic syndrome Pathogenic:1 Uncertain: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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	3.6
DANN	Benign	0.90
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.28
Sift	Benign	0.15	T
Sift4G	Uncertain	0.056	T
Polyphen		0.068	B
Vest4		0.17
MVP		0.31
ClinPred		0.015	T
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

Other links and lift over

dbSNP: rs1800578; hg19: chr20-23028659;