20-23045859-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000361.3(THBD):c.*1918G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 152,058 control chromosomes in the GnomAD database, including 43,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.76 (43709 hom., cov: 32)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: THBD NM_000361.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.500

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-23045859-C-T is Benign according to our data. Variant chr20-23045859-C-T is described in ClinVar as [Benign]. Clinvar id is 337852.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBD	NM_000361.3	c.*1918G>A		3_prime_UTR_variant	1/1	ENST00000377103.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBD	ENST00000377103.3	c.*1918G>A		3_prime_UTR_variant	1/1		NM_000361.3	P1

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114910 AN: 151938 Hom.: 43671 Cov.: 32

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.840

Gnomad FIN AF: 0.830

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.746

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.756 AC: 115002 AN: 152056 Hom.: 43709 Cov.: 32 AF XY: 0.763 AC XY: 56683 AN XY: 74338

Gnomad4 AFR AF: 0.708

Gnomad4 AMR AF: 0.754

Gnomad4 ASJ AF: 0.767

Gnomad4 EAS AF: 0.798

Gnomad4 SAS AF: 0.838

Gnomad4 FIN AF: 0.830

Gnomad4 NFE AF: 0.767

Gnomad4 OTH AF: 0.746

Alfa AF: 0.761 Hom.: 42734

Bravo AF: 0.746

Asia WGS AF: 0.811 AC: 2818 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atypical hemolytic-uremic syndrome with thrombomodulin anomaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.56
Dann	Benign	0.32

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: rs1962; hg19: chr20-23026496;