rs5350

Positions:

• chr13-77903226-G-A

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.731C>T​(p.Thr244Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000633 in 1,612,874 control chromosomes in the GnomAD database, including 10 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 0.0032 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (3 hom.)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.78

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 disulfide_bond (size 81) in uniprot entity EDNRB_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_001122659.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.008720815).
• BP6: Variant 13-77903226-G-A is Benign according to our data. Variant chr13-77903226-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255141.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr13-77903226-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00319 (484/151882) while in subpopulation AFR AF= 0.0108 (448/41456). AF 95% confidence interval is 0.00998. There are 7 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDNRB	NM_001122659.3	c.731C>T	p.Thr244Met	missense_variant	3/7	ENST00000646607.2	NP_001116131.1
EDNRB-AS1	NR_103853.1	n.1695-4466G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000646607.2	c.731C>T	p.Thr244Met	missense_variant	3/7		NM_001122659.3	ENSP00000493527	P1

Frequencies

GnomAD3 genomes AF: 0.00318 AC: 482 AN: 151764 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000801 AC: 201 AN: 250922 Hom.: 1 AF XY: 0.000546 AC XY: 74 AN XY: 135602

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000368 AC: 537 AN: 1460992 Hom.: 3 Cov.: 32 AF XY: 0.000325 AC XY: 236 AN XY: 726816

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00319 AC: 484 AN: 151882 Hom.: 7 Cov.: 32 AF XY: 0.00300 AC XY: 223 AN XY: 74238

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000682 Hom.: 3

Bravo AF: 0.00346

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Thr334Met in exon 4 of EDNRB: This variant is not expected to have clinical sign ificance because it has been identified in 1.2% (55/4406) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs5350). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2020	- -

Hirschsprung disease, susceptibility to, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	.;D;D;D;D;.;D;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.79	T;.;.;.;.;T;T;T;T
MetaRNN	Benign	0.0087	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.4	.;M;M;M;M;M;M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.6	D;.;.;D;.;.;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.058	T;.;.;T;.;.;.;.;.
Sift4G	Uncertain	0.026	D;.;.;T;.;T;.;.;.
Polyphen		1.0	D;D;D;D;D;D;D;.;.
Vest4		0.19
MVP		0.92
MPC		1.2
ClinPred		0.034	T
GERP RS		3.0
Varity_R		0.076
gMVP		0.79

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: rs5350; hg19: chr13-78477361; COSMIC: COSV57526494;