rs3176122

Variant names:

• chr20-23047280-C-T
• rs3176122
• NM_000361.3:c.*497G>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.*497G>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 0.00757 in 155,120 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: THBD NM_000361.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.553
• Publications: 2 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), PanelApp Australia
• thrombomodulin-related bleeding disorder

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000296483 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-23047280-C-T is Benign according to our data. Variant chr20-23047280-C-T is described in ClinVar as Benign. ClinVar VariationId is 337870.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00767 (1167/152134) while in subpopulation AFR AF = 0.0158 (657/41490). AF 95% confidence interval is 0.0148. There are 5 homozygotes in GnomAd4. There are 568 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000361.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBD	NM_000361.3	MANE Select	c.*497G>A		3_prime_UTR	Exon 1 of 1	NP_000352.1	P07204

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBD	ENST00000377103.3	TSL:6 MANE Select	c.*497G>A		3_prime_UTR	Exon 1 of 1	ENSP00000366307.2	P07204
	ENSG00000296483	ENST00000739851.1		n.795+3539G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1165 AN: 152016 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00957

GnomAD4 exome AF: 0.00234 AC: 7 AN: 2986 Hom.: 0 Cov.: 0 AF XY: 0.00127 AC XY: 2 AN XY: 1574

African (AFR) AF: 0.00 AC: 0 AN: 76

American (AMR) AF: 0.00 AC: 0 AN: 354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 74

East Asian (EAS) AF: 0.00 AC: 0 AN: 72

South Asian (SAS) AF: 0.00 AC: 0 AN: 190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 74

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00352 AC: 7 AN: 1990

Other (OTH) AF: 0.00 AC: 0 AN: 146

GnomAD4 genome AF: 0.00767 AC: 1167 AN: 152134 Hom.: 5 Cov.: 33 AF XY: 0.00764 AC XY: 568 AN XY: 74386

African (AFR) AF: 0.0158 AC: 657 AN: 41490

American (AMR) AF: 0.00602 AC: 92 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00340 AC: 36 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00509 AC: 346 AN: 68010

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.00601 Hom.: 3

Bravo AF: 0.00844

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Atypical hemolytic-uremic syndrome with thrombomodulin anomaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.58
PhyloP100		-0.55
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3176122;

hg19: chr20-23027917;