13-77975500-C-T

Position:

• chr13-77975500-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000435281.2(ENSG00000233379):​n.40G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 152,486 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (45 hom., cov: 33)
  • Exomes 𝑓: 0.034 (0 hom.)
• Consequence: ENST00000435281.2 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.940

Genes affected

(HGNC:):

OBI1-AS1 (HGNC:42700): (OBI1 antisense RNA 1)

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=-1.0).
• BP6: Variant 13-77975500-C-T is Benign according to our data. Variant chr13-77975500-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 880916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0143 (2184/152254) while in subpopulation EAS AF= 0.0246 (127/5172). AF 95% confidence interval is 0.0211. There are 45 homozygotes in gnomad4. There are 1178 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 45 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDNRB	NM_000115.5	c.-205G>A		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000435281.2	n.40G>A		non_coding_transcript_exon_variant	1/3	5
OBI1-AS1	ENST00000607862.5	n.230+55582C>T		intron_variant, non_coding_transcript_variant		1
EDNRB	ENST00000646948.1	c.-205G>A		5_prime_UTR_variant	1/8			P1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2183 AN: 152134 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00975

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.0245

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.0510

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.0345 AC: 8 AN: 232 Hom.: 0 Cov.: 0 AF XY: 0.0333 AC XY: 6 AN XY: 180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0421

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0143 AC: 2184 AN: 152254 Hom.: 45 Cov.: 33 AF XY: 0.0158 AC XY: 1178 AN XY: 74452

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.00974

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.0246

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.0510

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0234 Hom.: 13

Bravo AF: 0.00950

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.7
DANN	Benign	0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12720104; hg19: chr13-78549635;