rs3176134

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr20-23047500-C-T
• chr20-23047500-C-A
• chr20-23047500-C-G

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, multiple submitters, no conflicts B:2
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• thrombomodulin-related bleeding disorder

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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.

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.*277G>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.*277G>A		3_prime_UTR	Exon 1 of 1	ENSP00000366307.2	P07204
	ENSG00000296483	ENST00000739851.1		n.795+3319G>A		intron	N/A

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Atypical hemolytic-uremic syndrome with thrombomodulin anomaly (1)
-	-	1	Thrombomodulin-related bleeding disorder (1)

Computational scores

Source: dbNSFP v4.9

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;