rs1801710

Positions:

• chr13-77918405-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001122659.3(EDNRB):​c.169G>A​(p.Gly57Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 1,597,292 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0045 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0065 (44 hom.)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: -0.0970

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004221499).
• BP6: Variant 13-77918405-C-T is Benign according to our data. Variant chr13-77918405-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16637.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=5}. Variant chr13-77918405-C-T is described in Lovd as [Likely_benign]. Variant chr13-77918405-C-T is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00452 (687/152150) while in subpopulation NFE AF= 0.0079 (537/68014). AF 95% confidence interval is 0.00734. There are 1 homozygotes in gnomad4. There are 317 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 44 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDNRB	NM_001122659.3	c.169G>A	p.Gly57Ser	missense_variant	1/7	ENST00000646607.2	NP_001116131.1
EDNRB	NM_001201397.1	c.439G>A	p.Gly147Ser	missense_variant	2/8		NP_001188326.1
EDNRB	NM_000115.5	c.169G>A	p.Gly57Ser	missense_variant	2/8		NP_000106.1
EDNRB	NM_003991.4	c.169G>A	p.Gly57Ser	missense_variant	1/7		NP_003982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000646607.2	c.169G>A	p.Gly57Ser	missense_variant	1/7		NM_001122659.3	ENSP00000493527.1

Frequencies

GnomAD3 genomes AF: 0.00452 AC: 687 AN: 152032 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00643

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00789

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00513 AC: 1225 AN: 238706 Hom.: 9 AF XY: 0.00523 AC XY: 674 AN XY: 128756

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.000539

Gnomad FIN exome AF: 0.00649

Gnomad NFE exome AF: 0.00927

Gnomad OTH exome AF: 0.00384

GnomAD4 exome AF: 0.00654 AC: 9444 AN: 1445142 Hom.: 44 Cov.: 31 AF XY: 0.00640 AC XY: 4593 AN XY: 717122

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.000535

Gnomad4 ASJ exome AF: 0.000361

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000405

Gnomad4 FIN exome AF: 0.00845

Gnomad4 NFE exome AF: 0.00776

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.00452 AC: 687 AN: 152150 Hom.: 1 Cov.: 31 AF XY: 0.00426 AC XY: 317 AN XY: 74390

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00643

Gnomad4 NFE AF: 0.00790

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00656 Hom.: 10

Bravo AF: 0.00383

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.00620 AC: 753

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2018	This variant is associated with the following publications: (PMID: 21507037, 9760196, 8630503, 16618617, 24633486, 9721987, 9035203, 27148356, 16145050, 20031584, 16855133, 11302967, 10192234, 11471546, 8852660, 18758497, 16002759) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	EDNRB: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Gly147Ser in exon 2 of EDNRB: This variant is not expected to have clinical si gnificance because it has been identified in 0.9% (76/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs1801710). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hirschsprung disease, susceptibility to, 2 Benign:1 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.7
DANN	Benign	0.96
DEOGEN2	Benign	0.28	.;T;T;T;T;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.67	T;.;.;.;.;T;T;T
MetaRNN	Benign	0.0042	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L;L;L;L;L;L;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.14	N;.;.;N;.;.;.;.
REVEL	Benign	0.028
Sift	Benign	0.076	T;.;.;T;.;.;.;.
Sift4G	Benign	0.23	T;.;.;T;.;T;.;.
Polyphen		0.27	B;B;B;B;B;B;B;.
Vest4		0.052
MVP		0.38
MPC		0.46
ClinPred		0.00026	T
GERP RS		-0.44
Varity_R		0.10
gMVP		0.29

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: rs1801710; hg19: chr13-78492540; COSMIC: COSV100526052; COSMIC: COSV100526052;