rs5346

Positions:

• chr13-77918525-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_001122659.3(EDNRB):​c.49C>T​(p.Leu17Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,591,272 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L17P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.719

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004520476).
• BP6: Variant 13-77918525-G-A is Benign according to our data. Variant chr13-77918525-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226623.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr13-77918525-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00455 (693/152226) while in subpopulation AFR AF= 0.0159 (662/41546). AF 95% confidence interval is 0.0149. There are 5 homozygotes in gnomad4. There are 338 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDNRB	NM_001122659.3	c.49C>T	p.Leu17Phe	missense_variant	1/7	ENST00000646607.2
EDNRB	NM_001201397.1	c.319C>T	p.Leu107Phe	missense_variant	2/8
EDNRB	NM_000115.5	c.49C>T	p.Leu17Phe	missense_variant	2/8
EDNRB	NM_003991.4	c.49C>T	p.Leu17Phe	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDNRB	ENST00000646607.2	c.49C>T	p.Leu17Phe	missense_variant	1/7		NM_001122659.3	P1

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 690 AN: 152108 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00125 AC: 284 AN: 228090 Hom.: 0 AF XY: 0.000901 AC XY: 111 AN XY: 123142

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.000264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000386

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.000417 AC: 600 AN: 1439046 Hom.: 3 Cov.: 31 AF XY: 0.000361 AC XY: 258 AN XY: 714896

Gnomad4 AFR exome AF: 0.0162

Gnomad4 AMR exome AF: 0.000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000367

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000453

Gnomad4 OTH exome AF: 0.000793

GnomAD4 genome AF: 0.00455 AC: 693 AN: 152226 Hom.: 5 Cov.: 32 AF XY: 0.00454 AC XY: 338 AN XY: 74444

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000992 Hom.: 6

Bravo AF: 0.00497

ESP6500AA AF: 0.0172 AC: 76

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00146 AC: 177

Asia WGS AF: 0.000866 AC: 3 AN: 3478

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Leu107Phe in exon 2 of EDNRB: This variant is not expected to have clinical sign ificance because it has been identified in 1.7% (76/4406) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs5346). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2018	This variant is associated with the following publications: (PMID: 28236341) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	- -

Hirschsprung disease, susceptibility to, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	0.068
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	.;T;T;T;T;.;T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.71	T;.;.;.;.;T;T;T
MetaRNN	Benign	0.0045	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	.;L;L;L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.94	N;.;.;N;.;.;.;.
REVEL	Benign	0.082
Sift	Uncertain	0.021	D;.;.;T;.;.;.;.
Sift4G	Benign	0.10	T;.;.;T;.;T;.;.
Polyphen		0.0040	B;B;B;B;B;B;B;.
Vest4		0.056
MVP		0.89
MPC		0.50
ClinPred		0.0059	T
GERP RS		1.6
Varity_R		0.068
gMVP		0.27

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: rs5346; hg19: chr13-78492660;