rs5352

Positions:

chr13-77901095-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001122659.3(EDNRB):c.914G>A(p.Ser305Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0122 in 1,611,268 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 18 hom., cov: 32)

Exomes 𝑓: 0.012 ( 122 hom. )

Consequence

EDNRB
NM_001122659.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10O:1

Conservation

PhyloP100: 4.54

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 -11 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 27) in uniprot entity EDNRB_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001122659.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0069637).

BP6

Variant 13-77901095-C-T is Benign according to our data. Variant chr13-77901095-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16638.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=8, Uncertain_significance=1}. Variant chr13-77901095-C-T is described in Lovd as [Likely_benign]. Variant chr13-77901095-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0106 (1617/151928) while in subpopulation AMR AF= 0.0165 (251/15224). AF 95% confidence interval is 0.0148. There are 18 homozygotes in gnomad4. There are 827 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDNRB	NM_001122659.3 linkuse as main transcript	c.914G>A	p.Ser305Asn	missense_variant	4/7	ENST00000646607.2	NP_001116131.1
EDNRB-AS1	NR_103853.1 linkuse as main transcript	n.1695-6597C>T		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.914G>A	p.Ser305Asn	missense_variant	4/7		NM_001122659.3	ENSP00000493527	P1	P24530-1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1617

AN:

151810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00278

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0240

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.0101

GnomAD3 exomes

AF:

0.0100

AC:

2516

AN:

250600

Hom.:

AF XY:

0.0101

AC XY:

1372

AN XY:

135478

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.0121

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0199

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.0123

GnomAD4 exome

AF:

0.0123

AC:

18019

AN:

1459340

Hom.:

122

Cov.:

AF XY:

0.0120

AC XY:

8743

AN XY:

726064

show subpopulations

Gnomad4 AFR exome

AF:

0.00201

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.0143

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0211

Gnomad4 NFE exome

AF:

0.0138

Gnomad4 OTH exome

AF:

0.00961

GnomAD4 genome

AF:

0.0106

AC:

1617

AN:

151928

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

827

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.00277

Gnomad4 AMR

AF:

0.0165

Gnomad4 ASJ

AF:

0.0144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0240

Gnomad4 NFE

AF:

0.0133

Gnomad4 OTH

AF:

0.00996

Alfa

AF:

0.0125

Hom.:

Bravo

AF:

0.00990

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0138

AC:

119

ExAC

AF:

0.00886

AC:

1076

Asia WGS

AF:

0.000578

AC:

AN:

3472

EpiCase

AF:

0.0140

EpiControl

AF:

0.0148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2019	This variant is associated with the following publications: (PMID: 22995991, 26764160, 27535533, 10874640, 8852659, 21507037) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	EDNRB: BS1, BS2 -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ser395Asn in exon 5 of EDNRB: This variant is not expected to have clinical si gnificance because it has been identified in 1.4% (119/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs5352). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hirschsprung disease, susceptibility to, 2

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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, 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. -
risk factor, no assertion criteria provided	literature only	OMIM	Apr 01, 1999	- -

Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Ser305Asn variant, sometimes called p.Ser205Asn or p.Ser295Asn, in EDNRB has been identified in at least 6 individuals with Hirschsprung disease, including 4 relatives from 1 family (PMID: 8852659, 10874640, 22995991). However, this variant does not segregate with disease (PMID: 10874640), and has been identified in >2% of European (Finnish) chromosomes and 5 homozygotes in ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for Hirschsprung disease. -

Waardenburg syndrome type 2A

Benign:1

Likely benign, criteria provided, single submitter

research

Laboratory of Human Genetics, Universidade de São Paulo

Mar 01, 2017

- -

Waardenburg syndrome type 4A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.27

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

Eigen

Benign

-0.27

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.91

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

MetaRNN

Benign

0.0070

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

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

MutationTaster

Benign

0.94

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

1.5

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

REVEL

Benign

0.095

Sift

Benign

0.52

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

Sift4G

Benign

0.98

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

Polyphen

0.0030

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

Vest4

0.073

MPC

0.43

ClinPred

0.011

GERP RS

5.7

Varity_R

0.23

gMVP

0.35

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