NM_000361.3:c.*1001A>C

Variant names:

• chr20-23046776-T-G
• rs3176123
• NM_000361.3:c.*1001A>C

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.*1001A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,258 control chromosomes in the GnomAD database, including 2,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2242 hom., cov: 33)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: THBD NM_000361.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0870
• Publications: 34 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=-0.79).
• BP6: Variant 20-23046776-T-G is Benign according to our data. Variant chr20-23046776-T-G is described in ClinVar as Benign. ClinVar VariationId is 337862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 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.*1001A>C		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.*1001A>C		3_prime_UTR	Exon 1 of 1	ENSP00000366307.2	P07204
	ENSG00000296483	ENST00000739851.1		n.795+4043A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23471 AN: 152136 Hom.: 2244 Cov.: 33

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.0766

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

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: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.154 AC: 23467 AN: 152254 Hom.: 2242 Cov.: 33 AF XY: 0.160 AC XY: 11935 AN XY: 74434

African (AFR) AF: 0.0502 AC: 2087 AN: 41566

American (AMR) AF: 0.158 AC: 2413 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0766 AC: 266 AN: 3472

East Asian (EAS) AF: 0.305 AC: 1578 AN: 5178

South Asian (SAS) AF: 0.172 AC: 832 AN: 4834

European-Finnish (FIN) AF: 0.299 AC: 3163 AN: 10578

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12671 AN: 68006

Other (OTH) AF: 0.144 AC: 305 AN: 2116

Alfa AF: 0.175 Hom.: 9083

Bravo AF: 0.139

Asia WGS AF: 0.214 AC: 744 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	not provided (1)
-	-	1	Thrombomodulin-related bleeding disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		-0.087
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs3176123; hg19: chr20-23027413;