13-77896654-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001122659.3(EDNRB):c.*1546A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,489,870 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (87 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (63 hom.)
• Consequence: EDNRB NM_001122659.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.516

Genes affected

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]

EDNRB-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 13-77896654-T-C is Benign according to our data. Variant chr13-77896654-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 312454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDNRB	NM_001122659.3	c.*1546A>G		3_prime_UTR_variant	7/7	ENST00000646607.2
EDNRB-AS1	NR_103853.1	n.1695-11038T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDNRB	ENST00000646607.2	c.*1546A>G		3_prime_UTR_variant	7/7		NM_001122659.3	P1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2630 AN: 152008 Hom.: 86 Cov.: 33

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00276 AC: 3691 AN: 1337744 Hom.: 63 Cov.: 31 AF XY: 0.00254 AC XY: 1669 AN XY: 658230

Gnomad4 AFR exome AF: 0.0621

Gnomad4 AMR exome AF: 0.00862

Gnomad4 ASJ exome AF: 0.00547

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.0000796

Gnomad4 NFE exome AF: 0.000984

Gnomad4 OTH exome AF: 0.00710

GnomAD4 genome AF: 0.0173 AC: 2638 AN: 152126 Hom.: 87 Cov.: 33 AF XY: 0.0164 AC XY: 1216 AN XY: 74356

Gnomad4 AFR AF: 0.0562

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00964 Hom.: 12

Bravo AF: 0.0201

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hirschsprung disease, susceptibility to, 2 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	14
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs3027094; hg19: chr13-78470789;