rs5350

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001122659.3(EDNRB):c.731C>T(p.Thr244Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000633 in 1,612,874 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T244T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

EDNRB
NM_001122659.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.78

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 -11 ACMG points.

PM1

In a disulfide_bond (size 81) in uniprot entity EDNRB_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_001122659.3

BP4

Computational evidence support a benign effect (MetaRNN=0.008720815).

BP6

Variant 13-77903226-G-A is Benign according to our data. Variant chr13-77903226-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255141.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}. Variant chr13-77903226-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00319 (484/151882) while in subpopulation AFR AF = 0.0108 (448/41456). AF 95% confidence interval is 0.00998. There are 7 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRB	NM_001122659.3 link	c.731C>T	p.Thr244Met	missense_variant	Exon 3 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.731C>T	p.Thr244Met	missense_variant	Exon 3 of 7		NM_001122659.3	ENSP00000493527.1		P24530-1

Frequencies

GnomAD3 genomes

AF:

0.00318

AC:

482

AN:

151764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000801

AC:

201

AN:

250922

AF XY:

0.000546

show subpopulations

Gnomad AFR exome

AF:

0.0107

Gnomad AMR exome

AF:

0.000522

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000368

AC:

537

AN:

1460992

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

236

AN XY:

726816

show subpopulations

Gnomad4 AFR exome

AF:

0.0113

AC:

376

AN:

33408

Gnomad4 AMR exome

AF:

0.000627

AC:

AN:

44634

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26092

Gnomad4 EAS exome

AF:

0.000126

AC:

AN:

39676

Gnomad4 SAS exome

AF:

0.000104

AC:

AN:

86242

Gnomad4 FIN exome

AF:

0.0000187

AC:

AN:

53394

Gnomad4 NFE exome

AF:

0.0000405

AC:

AN:

1111462

Gnomad4 Remaining exome

AF:

0.00113

AC:

AN:

60324

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.00319

AC:

484

AN:

151882

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

223

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.0108

AC:

0.0108066

AN:

0.0108066

Gnomad4 AMR

AF:

0.00157

AC:

0.00157418

AN:

0.00157418

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000195

AC:

0.000194704

AN:

0.000194704

Gnomad4 SAS

AF:

0.000417

AC:

0.000416667

AN:

0.000416667

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000589

AC:

0.0000589362

AN:

0.0000589362

Gnomad4 OTH

AF:

0.00236

AC:

0.00236295

AN:

0.00236295

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<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:

0.00116

Hom.:

Bravo

AF:

0.00346

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00105

AC:

127

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr334Met in exon 4 of EDNRB: This variant is not expected to have clinical sign ificance because it has been identified in 1.2% (55/4406) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs5350). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 17, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hirschsprung disease, susceptibility to, 2

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

.;D;D;D;D;.;D;.;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.79

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

MetaRNN

Benign

0.0087

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

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.4

.;M;M;M;M;M;M;.;.

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.6

D;.;.;D;.;.;.;.;.

REVEL

Benign

0.24

Sift

Benign

0.058

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

Sift4G

Uncertain

0.026

D;.;.;T;.;T;.;.;.

Polyphen

1.0

D;D;D;D;D;D;D;.;.

Vest4

0.19

MVP

0.92

MPC

1.2

ClinPred

0.034

GERP RS

3.0

Varity_R

0.076

gMVP

0.79

Mutation Taster

=89/11

polymorphism

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