13-77975416-C-A

Position:

• chr13-77975416-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000115.5(EDNRB):​c.-121G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 152,200 control chromosomes in the GnomAD database, including 5,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5848 hom., cov: 32)
  • Exomes 𝑓: 0.20 (2 hom.)
• Consequence: EDNRB NM_000115.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.72

Genes affected

OBI1-AS1 (HGNC:):

EDNRB (HGNC:3180): (endothelin receptor type B) The protein encoded by this gene is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three potent vasoactive peptides: ET1, ET2, and ET3. Studies suggest that the multigenic disorder, Hirschsprung disease type 2, is due to mutations in the endothelin receptor type B gene. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 13-77975416-C-A is Benign according to our data. Variant chr13-77975416-C-A is described in ClinVar as [Benign]. Clinvar id is 884206.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDNRB	NM_000115.5	c.-121G>T		5_prime_UTR_premature_start_codon_gain_variant	1/8		NP_000106.1
EDNRB	NM_000115.5	c.-121G>T		5_prime_UTR_variant	1/8		NP_000106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OBI1-AS1	ENST00000607862.5	n.230+55498C>A		intron_variant		1
EDNRB	ENST00000646948.1	c.-121G>T		5_prime_UTR_premature_start_codon_gain_variant	1/8			ENSP00000493895.1
EDNRB	ENST00000646948.1	c.-121G>T		5_prime_UTR_variant	1/8			ENSP00000493895.1

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37665 AN: 151960 Hom.: 5823 Cov.: 32

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.197 AC: 24 AN: 122 Hom.: 2 Cov.: 0 AF XY: 0.181 AC XY: 17 AN XY: 94

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.00

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.248 AC: 37738 AN: 152078 Hom.: 5848 Cov.: 32 AF XY: 0.251 AC XY: 18687 AN XY: 74356

Gnomad4 AFR AF: 0.399

Gnomad4 AMR AF: 0.275

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.538

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.228

Alfa AF: 0.0676 Hom.: 77

Bravo AF: 0.264

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hirschsprung disease, susceptibility to, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.062
DANN	Benign	0.63

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12720105; hg19: chr13-78549551;