20-23045859-C-T

Variant names:

• chr20-23045859-C-T
• rs1962
• NM_000361.3:c.*1918G>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.*1918G>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 0.756 in 152,058 control chromosomes in the GnomAD database, including 43,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (43709 hom., cov: 32)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: THBD NM_000361.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.500
• Publications: 19 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=-0.86).
• BP6: Variant 20-23045859-C-T is Benign according to our data. Variant chr20-23045859-C-T is described in ClinVar as Benign. ClinVar VariationId is 337852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.817 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBD	NM_000361.3	MANE Select	c.*1918G>A		3_prime_UTR	Exon 1 of 1	NP_000352.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBD	ENST00000377103.3	TSL:6 MANE Select	c.*1918G>A		3_prime_UTR	Exon 1 of 1	ENSP00000366307.2
	ENSG00000296483	ENST00000739851.1		n.796-4108G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114910 AN: 151938 Hom.: 43671 Cov.: 32

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.840

Gnomad FIN AF: 0.830

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.746

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.756 AC: 115002 AN: 152056 Hom.: 43709 Cov.: 32 AF XY: 0.763 AC XY: 56683 AN XY: 74338

African (AFR) AF: 0.708 AC: 29345 AN: 41442

American (AMR) AF: 0.754 AC: 11530 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 2662 AN: 3470

East Asian (EAS) AF: 0.798 AC: 4120 AN: 5166

South Asian (SAS) AF: 0.838 AC: 4038 AN: 4816

European-Finnish (FIN) AF: 0.830 AC: 8790 AN: 10588

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.767 AC: 52159 AN: 67966

Other (OTH) AF: 0.746 AC: 1578 AN: 2114

Alfa AF: 0.759 Hom.: 55401

Bravo AF: 0.746

Asia WGS AF: 0.811 AC: 2818 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Atypical hemolytic-uremic syndrome with thrombomodulin anomaly (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.56
DANN	Benign	0.32
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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: rs1962; hg19: chr20-23026496;