NM_000361.3:c.*277G>A

Variant names:

• chr20-23047500-C-T
• rs3176134
• NM_000361.3:c.*277G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000361.3(THBD):​c.*277G>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 0.0104 in 536,092 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (38 hom., cov: 33)
  • Exomes 𝑓: 0.011 (170 hom.)
• Consequence: THBD NM_000361.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0180
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 20-23047500-C-T is Benign according to our data. Variant chr20-23047500-C-T is described in ClinVar as Benign. ClinVar VariationId is 337875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THBD	NM_000361.3	c.*277G>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.*277G>A		3_prime_UTR_variant	Exon 1 of 1	6	NM_000361.3	ENSP00000366307.2
ENSG00000296483	ENST00000739851.1	n.795+3319G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00971 AC: 1477 AN: 152186 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00955

GnomAD4 exome AF: 0.0107 AC: 4093 AN: 383788 Hom.: 170 Cov.: 3 AF XY: 0.0106 AC XY: 2122 AN XY: 199510

African (AFR) AF: 0.0146 AC: 163 AN: 11196

American (AMR) AF: 0.00596 AC: 83 AN: 13930

Ashkenazi Jewish (ASJ) AF: 0.000568 AC: 7 AN: 12314

East Asian (EAS) AF: 0.101 AC: 2810 AN: 27742

South Asian (SAS) AF: 0.0172 AC: 554 AN: 32196

European-Finnish (FIN) AF: 0.0000379 AC: 1 AN: 26380

Middle Eastern (MID) AF: 0.00577 AC: 10 AN: 1732

European-Non Finnish (NFE) AF: 0.00119 AC: 279 AN: 235374

Other (OTH) AF: 0.00811 AC: 186 AN: 22924

GnomAD4 genome AF: 0.00968 AC: 1474 AN: 152304 Hom.: 38 Cov.: 33 AF XY: 0.0105 AC XY: 784 AN XY: 74474

African (AFR) AF: 0.0158 AC: 655 AN: 41542

American (AMR) AF: 0.00464 AC: 71 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.105 AC: 546 AN: 5190

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00123 AC: 84 AN: 68032

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.00603 Hom.: 11

Bravo AF: 0.0110

Asia WGS AF: 0.0430 AC: 150 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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.78
CADD	Benign	4.7
DANN	Benign	0.68
PhyloP100		0.018
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: rs3176134; hg19: chr20-23028137;