rs1800577

Positions:

• chr20-23049269-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000361.3(THBD):​c.236G>C​(p.Gly79Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,551,110 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: THBD NM_000361.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.0980

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07544395).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THBD	NM_000361.3	c.236G>C	p.Gly79Ala	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	c.236G>C	p.Gly79Ala	missense_variant	1/1	6	NM_000361.3	ENSP00000366307.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000136 AC: 2 AN: 146520 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 80218

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000425

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000175

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000114 AC: 16 AN: 1398858 Hom.: 0 Cov.: 51 AF XY: 0.0000116 AC XY: 8 AN XY: 690802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000288

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000129

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000276 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 809235). This variant is also known as Gly61Ala. This missense change has been observed in individual(s) with thromboembolic disease (PMID: 9198186). This variant is present in population databases (rs1800577, gnomAD 0.004%). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 79 of the THBD protein (p.Gly79Ala). -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2019	- -

Atypical hemolytic-uremic syndrome with thrombomodulin anomaly;C3280976:Thrombomodulin-related bleeding disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.3
DANN	Benign	0.32
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.26
Sift	Benign	0.82	T
Sift4G	Benign	1.0	T
Polyphen		0.020	B
Vest4		0.14
MutPred		0.15		Gain of MoRF binding (P = 0.1634);
MVP		0.36
ClinPred		0.041	T
GERP RS		3.4
Varity_R		0.076
gMVP		0.27

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: rs1800577; hg19: chr20-23029906;