chr13-77896433-G-A

Position:

chr13-77896433-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001122659.3(EDNRB):c.*1767C>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 0.0136 in 1,554,920 control chromosomes in the GnomAD database, including 255 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 ( 44 hom., cov: 32)

Exomes 𝑓: 0.013 ( 211 hom. )

Consequence

EDNRB
NM_001122659.3 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.225

Variant links:

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 links:

EDNRB-AS1 (HGNC:):

EDNRB-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 13-77896433-G-A is Benign according to our data. Variant chr13-77896433-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0144 (2197/152064) while in subpopulation EAS AF= 0.0259 (133/5138). AF 95% confidence interval is 0.0223. There are 44 homozygotes in gnomad4. There are 1181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 44 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDNRB	NM_001122659.3 linkuse as main transcript	c.*1767C>T		3_prime_UTR_variant	7/7	ENST00000646607.2	NP_001116131.1
EDNRB-AS1	NR_103853.1 linkuse as main transcript	n.1695-11259G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000646607.2 linkuse as main transcript	c.*1767C>T		3_prime_UTR_variant	7/7		NM_001122659.3	ENSP00000493527	P1	P24530-1

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2197

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00926

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.0258

Gnomad SAS

AF:

0.0156

Gnomad FIN

AF:

0.0511

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0170

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0156

AC:

2636

AN:

169286

Hom.:

AF XY:

0.0158

AC XY:

1421

AN XY:

89872

show subpopulations

Gnomad AFR exome

AF:

0.00194

Gnomad AMR exome

AF:

0.00498

Gnomad ASJ exome

AF:

0.00975

Gnomad EAS exome

AF:

0.0213

Gnomad SAS exome

AF:

0.0130

Gnomad FIN exome

AF:

0.0490

Gnomad NFE exome

AF:

0.0144

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.0135

AC:

18876

AN:

1402856

Hom.:

211

Cov.:

AF XY:

0.0138

AC XY:

9584

AN XY:

692584

show subpopulations

Gnomad4 AFR exome

AF:

0.00152

Gnomad4 AMR exome

AF:

0.00488

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.0156

Gnomad4 SAS exome

AF:

0.0135

Gnomad4 FIN exome

AF:

0.0426

Gnomad4 NFE exome

AF:

0.0127

Gnomad4 OTH exome

AF:

0.0142

GnomAD4 genome

AF:

0.0144

AC:

2197

AN:

152064

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1181

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00200

Gnomad4 AMR

AF:

0.00925

Gnomad4 ASJ

AF:

0.0109

Gnomad4 EAS

AF:

0.0259

Gnomad4 SAS

AF:

0.0156

Gnomad4 FIN

AF:

0.0511

Gnomad4 NFE

AF:

0.0170

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.0130

Hom.:

Bravo

AF:

0.00958

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

*9C>T in exon 7B of EDNRB: This variant is not expected to have clinical signifi cance because it has been identified in 1.2% (101/8104) of European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs3027092). -

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

-0.82

CADD

Benign

1.6

DANN

Benign

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over