Variant rs201115708 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001201397.1(EDNRB):c.11G>C(p.Ser4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000928 in 1,606,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

EDNRB
NM_001201397.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.27

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12991723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDNRB	NM_001201397.1 linkuse as main transcript	c.11G>C	p.Ser4Thr	missense_variant	1/8		NP_001188326.1	P24530-3A0A024R638
EDNRB	NM_000115.5 linkuse as main transcript	c.-51-981G>C		intron_variant			NP_000106.1	P24530-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000377211.8 linkuse as main transcript	c.11G>C	p.Ser4Thr	missense_variant	1/8	1		ENSP00000366416.4		P24530-3
EDNRB	ENST00000646948.1 linkuse as main transcript	c.-51-981G>C		intron_variant				ENSP00000493895.1		P24530-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.0000922

AC:

AN:

238610

Hom.:

AF XY:

0.0000993

AC XY:

AN XY:

130944

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000205

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000887

AC:

129

AN:

1454302

Hom.:

Cov.:

AF XY:

0.0000886

AC XY:

AN XY:

722070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000867

Gnomad4 OTH exome

AF:

0.000250

GnomAD4 genome

AF:

0.000131

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.000189

ExAC

AF:

0.0000684

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 04, 2016

The p.Ser4Thr variant in EDNRB has not been previously reported in individuals w ith hearing loss or Waardenburg syndrome, but has been identified in 6/51196 of European chromosomes and 2/8742 of Latino chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201115708). Although th is variant has been seen in the general population, its frequency is not high en ough to rule out a pathogenic role. Computational prediction tools and conservat ion analysis do not provide strong support for or against an impact to the prote in. In summary, the clinical significance of the p.Ser4Thr variant is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.24

M_CAP

Benign

0.062

MetaRNN

Benign

0.13

MetaSVM

Uncertain

0.043

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.040

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Vest4

0.20

MutPred

0.13

Gain of sheet (P = 0.0477);

MVP

0.66

MPC

0.41

ClinPred

0.75

GERP RS

4.3

gMVP

0.061

Splicing

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