NM_001122659.3:c.169G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001122659.3(EDNRB):c.169G>A(p.Gly57Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 1,597,292 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G57D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0045 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0065 ( 44 hom. )

Consequence

EDNRB
NM_001122659.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8O:1

Conservation

PhyloP100: -0.0970

Publications

22 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 Gene-Disease associations (from GenCC):

ABCD syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Waardenburg syndrome type 4A
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
Waardenburg syndrome type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Waardenburg-Shah syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hirschsprung disease, susceptibility to, 2
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

EDNRB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004221499).

BP6

Variant 13-77918405-C-T is Benign according to our data. Variant chr13-77918405-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16637.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00452 (687/152150) while in subpopulation NFE AF = 0.0079 (537/68014). AF 95% confidence interval is 0.00734. There are 1 homozygotes in GnomAd4. There are 317 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 44 AD,AR,Unknown,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
EDNRB	NM_001122659.3 link	c.169G>A	p.Gly57Ser	missense_variant	Exon 1 of 7	ENST00000646607.2	NP_001116131.1
EDNRB	NM_001201397.2 link	c.439G>A	p.Gly147Ser	missense_variant	Exon 2 of 8		NP_001188326.1
EDNRB	NM_000115.5 link	c.169G>A	p.Gly57Ser	missense_variant	Exon 2 of 8		NP_000106.1
EDNRB	NM_003991.4 link	c.169G>A	p.Gly57Ser	missense_variant	Exon 1 of 7		NP_003982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000646607.2 link	c.169G>A	p.Gly57Ser	missense_variant	Exon 1 of 7		NM_001122659.3	ENSP00000493527.1

Frequencies

GnomAD3 genomes

AF:

0.00452

AC:

687

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00643

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00789

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00513

AC:

1225

AN:

238706

AF XY:

0.00523

show subpopulations

Gnomad AFR exome

AF:

0.00143

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.000117

Gnomad EAS exome

AF:

0.0000553

Gnomad FIN exome

AF:

0.00649

Gnomad NFE exome

AF:

0.00927

Gnomad OTH exome

AF:

0.00384

GnomAD4 exome

AF:

0.00654

AC:

9444

AN:

1445142

Hom.:

Cov.:

AF XY:

0.00640

AC XY:

4593

AN XY:

717122

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

32794

American (AMR)

AF:

0.000535

AC:

AN:

43026

Ashkenazi Jewish (ASJ)

AF:

0.000361

AC:

AN:

24906

East Asian (EAS)

AF:

0.000101

AC:

AN:

39498

South Asian (SAS)

AF:

0.000405

AC:

AN:

83958

European-Finnish (FIN)

AF:

0.00845

AC:

446

AN:

52788

Middle Eastern (MID)

AF:

0.000881

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.00776

AC:

8562

AN:

1102986

Other (OTH)

AF:

0.00533

AC:

317

AN:

59510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

638

1276

1913

2551

3189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

302

604

906

1208

1510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00452

AC:

687

AN:

152150

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

317

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41526

American (AMR)

AF:

0.00111

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.000208

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00643

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00790

AC:

537

AN:

68014

Other (OTH)

AF:

0.00332

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00674

Hom.:

Bravo

AF:

0.00383

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00884

AC:

ExAC

AF:

0.00620

AC:

753

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21507037, 9760196, 8630503, 16618617, 24633486, 9721987, 9035203, 27148356, 16145050, 20031584, 16855133, 11302967, 10192234, 11471546, 8852660, 18758497, 16002759) -

Feb 10, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EDNRB: BP4, BS2 -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gly147Ser in exon 2 of EDNRB: This variant is not expected to have clinical si gnificance because it has been identified in 0.9% (76/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs1801710). -

Jun 22, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hirschsprung disease, susceptibility to, 2

Benign:1Other:1

Aug 01, 1998

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.7

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.28

.;T;T;T;T;.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.67

T;.;.;.;.;T;T;T

MetaRNN

Benign

0.0042

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;L;L;L;L;L;L;.

PhyloP100

-0.097

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.14

N;.;.;N;.;.;.;.

REVEL

Benign

0.028

Sift

Benign

0.076

T;.;.;T;.;.;.;.

Sift4G

Benign

0.23

T;.;.;T;.;T;.;.

Polyphen

0.27

B;B;B;B;B;B;B;.

Vest4

0.052

MVP

0.38

MPC

0.46

ClinPred

0.00026

GERP RS

-0.44

PromoterAI

0.021

Neutral

(source)

Varity_R

0.10

gMVP

0.29

Mutation Taster

=96/4

polymorphism

(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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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