NM_001122659.3:c.*1767C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

Publications

4 publications found

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:49045): (EDNRB antisense RNA 1)

EDNRB-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

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

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 44 AD,AR,Unknown,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRB	NM_001122659.3 link	c.*1767C>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000646607.2	NP_001116131.1	P24530-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000646607.2 link	c.*1767C>T		3_prime_UTR_variant	Exon 7 of 7		NM_001122659.3	ENSP00000493527.1		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

GnomAD2 exomes

AF:

0.0156

AC:

2636

AN:

169286

AF XY:

0.0158

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 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

African (AFR)

AF:

0.00152

AC:

AN:

32156

American (AMR)

AF:

0.00488

AC:

178

AN:

36494

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

256

AN:

25324

East Asian (EAS)

AF:

0.0156

AC:

580

AN:

37194

South Asian (SAS)

AF:

0.0135

AC:

1073

AN:

79444

European-Finnish (FIN)

AF:

0.0426

AC:

2117

AN:

49708

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

4062

European-Non Finnish (NFE)

AF:

0.0127

AC:

13755

AN:

1080534

Other (OTH)

AF:

0.0142

AC:

823

AN:

57940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

857

1714

2570

3427

4284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0144

AC:

2197

AN:

152064

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1181

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

41522

American (AMR)

AF:

0.00925

AC:

141

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

AN:

3472

East Asian (EAS)

AF:

0.0259

AC:

133

AN:

5138

South Asian (SAS)

AF:

0.0156

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0511

AC:

542

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0170

AC:

1155

AN:

67952

Other (OTH)

AF:

0.0133

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

107

214

321

428

535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Jun 06, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 04, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

*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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.28

PhyloP100

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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NM_001122659.3:c.*1767C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over