20-23047619-C-T

Variant names:

• chr20-23047619-C-T
• rs3176121
• NM_000361.3:c.*158G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000361.3(THBD):​c.*158G>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 0.00169 in 870,340 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: THBD NM_000361.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0420
• Publications: 1 publications found

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]

THBD Gene-Disease associations (from GenCC):

• atypical hemolytic-uremic syndrome with thrombomodulin anomaly

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• thrombomodulin-related bleeding disorder

  Inheritance: AR, AD, Unknown Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ENSG00000296483 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 20-23047619-C-T is Benign according to our data. Variant chr20-23047619-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 337876.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00115 (175/152316) while in subpopulation NFE AF = 0.00213 (145/68026). AF 95% confidence interval is 0.00185. There are 1 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THBD	NM_000361.3	c.*158G>A		3_prime_UTR_variant	Exon 1 of 1	ENST00000377103.3	NP_000352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THBD	ENST00000377103.3	c.*158G>A		3_prime_UTR_variant	Exon 1 of 1	6	NM_000361.3	ENSP00000366307.2
ENSG00000296483	ENST00000739851.1	n.795+3200G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152198 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00180 AC: 1292 AN: 718024 Hom.: 3 Cov.: 9 AF XY: 0.00169 AC XY: 614 AN XY: 363530

African (AFR) AF: 0.000229 AC: 4 AN: 17494

American (AMR) AF: 0.000646 AC: 13 AN: 20128

Ashkenazi Jewish (ASJ) AF: 0.00271 AC: 42 AN: 15478

East Asian (EAS) AF: 0.0000310 AC: 1 AN: 32222

South Asian (SAS) AF: 0.00 AC: 0 AN: 51474

European-Finnish (FIN) AF: 0.000570 AC: 17 AN: 29822

Middle Eastern (MID) AF: 0.00121 AC: 3 AN: 2488

European-Non Finnish (NFE) AF: 0.00225 AC: 1157 AN: 514088

Other (OTH) AF: 0.00158 AC: 55 AN: 34830

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152316 Hom.: 1 Cov.: 33 AF XY: 0.000940 AC XY: 70 AN XY: 74468

African (AFR) AF: 0.000289 AC: 12 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00213 AC: 145 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00110

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atypical hemolytic-uremic syndrome with thrombomodulin anomaly Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.4
DANN	Benign	0.60
PhyloP100		0.042
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3176121; hg19: chr20-23028256;