13-77901095-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

3
15

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-AS1 (HGNC:49045): (EDNRB antisense RNA 1)

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: {Uncertain_significance=1, Benign=8, Likely_benign=2}. 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 rank MANE Protein UniProt
EDNRBNM_001122659.3 linkc.914G>A p.Ser305Asn missense_variant Exon 4 of 7 ENST00000646607.2 NP_001116131.1 P24530-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EDNRBENST00000646607.2 linkc.914G>A p.Ser305Asn missense_variant Exon 4 of 7 NM_001122659.3 ENSP00000493527.1 P24530-1

Frequencies

GnomAD3 genomes
AF:
0.0107
AC:
1617
AN:
151810
Hom.:
18
Cov.:
32
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.:
16
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.:
30
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.:
18
Cov.:
32
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.:
28
Bravo
AF:
0.00990
TwinsUK
AF:
0.0108
AC:
40
ALSPAC
AF:
0.0112
AC:
43
ESP6500AA
AF:
0.00204
AC:
9
ESP6500EA
AF:
0.0138
AC:
119
ExAC
AF:
0.00886
AC:
1076
Asia WGS
AF:
0.000578
AC:
2
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
Dec 29, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

EDNRB: BS1, BS2 -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 10, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22995991, 26764160, 27535533, 10874640, 8852659, 21507037) -

not specified Benign:3
May 10, 2017
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: 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.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). -

Hirschsprung disease, susceptibility to, 2 Uncertain:1Other:1
Apr 01, 1999
OMIM
Significance: risk factor
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mar 06, 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. -

Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant Benign:1
-
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research

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
Mar 01, 2017
Laboratory of Human Genetics, Universidade de São Paulo
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

Waardenburg syndrome type 4A Benign:1
Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.60
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
19
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
D
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
T
MutationAssessor
Benign
-1.0
.;N;N;N;N;N;N;.;.
PrimateAI
Uncertain
0.76
T
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
T
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.

Other links and lift over

dbSNP: rs5352; hg19: chr13-78475230; API