rs3176123

chr20-23046776-T-G

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.*1001A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,258 control chromosomes in the GnomAD database, including 2,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2242 hom., cov: 33)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: THBD NM_000361.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0870

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=-0.79).
• BP6: Variant 20-23046776-T-G is Benign according to our data. Variant chr20-23046776-T-G is described in ClinVar as [Benign]. Clinvar id is 337862.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBD	NM_000361.3	c.*1001A>C		3_prime_UTR_variant	1/1	ENST00000377103.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBD	ENST00000377103.3	c.*1001A>C		3_prime_UTR_variant	1/1		NM_000361.3	P1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23471 AN: 152136 Hom.: 2244 Cov.: 33

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.0766

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.154 AC: 23467 AN: 152254 Hom.: 2242 Cov.: 33 AF XY: 0.160 AC XY: 11935 AN XY: 74434

Gnomad4 AFR AF: 0.0502

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.0766

Gnomad4 EAS AF: 0.305

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.186

Gnomad4 OTH AF: 0.144

Alfa AF: 0.174 Hom.: 3817

Bravo AF: 0.139

Asia WGS AF: 0.214 AC: 744 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	-0.79
Cadd	Benign	11
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs3176123; hg19: chr20-23027413;