rs3176124

Variant names:

• chr20-23046308-G-A
• rs3176124
• NM_000361.3:c.*1469C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000361.3(THBD):​c.*1469C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 152,480 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (0 hom.)
• Consequence: THBD NM_000361.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.185
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 20-23046308-G-A is Benign according to our data. Variant chr20-23046308-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 337857.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00345 (526/152250) while in subpopulation NFE AF = 0.00507 (345/68008). AF 95% confidence interval is 0.00463. There are 2 homozygotes in GnomAd4. There are 273 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBD	NM_000361.3	MANE Select	c.*1469C>T		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.*1469C>T		3_prime_UTR	Exon 1 of 1	ENSP00000366307.2
	ENSG00000296483	ENST00000739851.1		n.795+4511C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152132 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

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: 0.00507

Gnomad OTH AF: 0.00670

GnomAD4 exome AF: 0.00435 AC: 1 AN: 230 Hom.: 0 Cov.: 0 AF XY: 0.00806 AC XY: 1 AN XY: 124

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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) AF: 0.00435 AC: 1 AN: 230

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00345 AC: 526 AN: 152250 Hom.: 2 Cov.: 33 AF XY: 0.00367 AC XY: 273 AN XY: 74434

African (AFR) AF: 0.000915 AC: 38 AN: 41550

American (AMR) AF: 0.00503 AC: 77 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00340 AC: 36 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00507 AC: 345 AN: 68008

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00465 Hom.: 1

Bravo AF: 0.00338

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	-0.68
CADD	Benign	13
DANN	Benign	0.69
PhyloP100		-0.18

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: rs3176124; hg19: chr20-23026945;