rs5349

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001122659.3(EDNRB):​c.561C>T​(p.Ile187=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00468 in 1,612,902 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 23 hom., cov: 32)
Exomes 𝑓: 0.0040 ( 41 hom. )

Consequence

EDNRB
NM_001122659.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.84
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.29).
BP6
Variant 13-77903530-G-A is Benign according to our data. Variant chr13-77903530-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1643/152036) while in subpopulation AFR AF= 0.0282 (1171/41518). AF 95% confidence interval is 0.0269. There are 23 homozygotes in gnomad4. There are 766 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 23 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EDNRBNM_001122659.3 linkuse as main transcriptc.561C>T p.Ile187= synonymous_variant 2/7 ENST00000646607.2 NP_001116131.1
EDNRB-AS1NR_103853.1 linkuse as main transcriptn.1695-4162G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EDNRBENST00000646607.2 linkuse as main transcriptc.561C>T p.Ile187= synonymous_variant 2/7 NM_001122659.3 ENSP00000493527 P1P24530-1

Frequencies

GnomAD3 genomes
AF:
0.0108
AC:
1635
AN:
151918
Hom.:
22
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0280
Gnomad AMI
AF:
0.0121
Gnomad AMR
AF:
0.00623
Gnomad ASJ
AF:
0.0254
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.00358
Gnomad OTH
AF:
0.0125
GnomAD3 exomes
AF:
0.00548
AC:
1373
AN:
250324
Hom.:
9
AF XY:
0.00502
AC XY:
679
AN XY:
135290
show subpopulations
Gnomad AFR exome
AF:
0.0289
Gnomad AMR exome
AF:
0.00563
Gnomad ASJ exome
AF:
0.0234
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000588
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.00370
Gnomad OTH exome
AF:
0.00589
GnomAD4 exome
AF:
0.00404
AC:
5903
AN:
1460866
Hom.:
41
Cov.:
31
AF XY:
0.00389
AC XY:
2830
AN XY:
726764
show subpopulations
Gnomad4 AFR exome
AF:
0.0316
Gnomad4 AMR exome
AF:
0.00599
Gnomad4 ASJ exome
AF:
0.0227
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000673
Gnomad4 FIN exome
AF:
0.000225
Gnomad4 NFE exome
AF:
0.00310
Gnomad4 OTH exome
AF:
0.00676
GnomAD4 genome
AF:
0.0108
AC:
1643
AN:
152036
Hom.:
23
Cov.:
32
AF XY:
0.0103
AC XY:
766
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.0282
Gnomad4 AMR
AF:
0.00623
Gnomad4 ASJ
AF:
0.0254
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00358
Gnomad4 OTH
AF:
0.0123
Alfa
AF:
0.00790
Hom.:
9
Bravo
AF:
0.0121
Asia WGS
AF:
0.00606
AC:
22
AN:
3478
EpiCase
AF:
0.00442
EpiControl
AF:
0.00551

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 13, 2015p.Ile277Ile in exon 3 of EDNRB: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 2.9% (128/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs5349). -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 09, 2017- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMar 03, 2021- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxMay 24, 2018This variant is associated with the following publications: (PMID: 17618893, 12628594, 22993632, 20009762) -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Hirschsprung disease, susceptibility to, 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.29
CADD
Benign
12
DANN
Benign
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs5349; hg19: chr13-78477665; API