rs5352

chr13-77901095-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10 O:1
• Conservation: PhyloP100: 4.54

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:):

ACMG classification

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 2 benign (75%) 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, Likely_benign=2, Benign=8}. 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 GnomAd at 18 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDNRB	NM_001122659.3	c.914G>A	p.Ser305Asn	missense_variant	4/7	ENST00000646607.2
EDNRB-AS1	NR_103853.1	n.1695-6597C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDNRB	ENST00000646607.2	c.914G>A	p.Ser305Asn	missense_variant	4/7		NM_001122659.3	P1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1617 AN: 151810 Hom.: 18 Cov.: 32

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

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

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

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:1 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	EDNRB: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2018	- -
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	Invitae	Jan 29, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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). -

Hirschsprung disease, susceptibility to, 2 Uncertain:1 Other: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	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	19
Dann	Benign	0.63
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
MutationTaster	Benign	0.94	D;D;D
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

Other links and lift over

dbSNP: rs5352; hg19: chr13-78475230;