13-77919609-T-A

Position:

• chr13-77919609-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000377211.8(EDNRB):​c.7A>T​(p.Lys3Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDNRB ENST00000377211.8 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.668

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 74 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDNRB	NM_001201397.1	c.7A>T	p.Lys3Ter	stop_gained	1/8		NP_001188326.1
EDNRB	NM_000115.5	c.-51-985A>T		intron_variant			NP_000106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000377211.8	c.7A>T	p.Lys3Ter	stop_gained	1/8	1		ENSP00000366416
EDNRB	ENST00000646948.1	c.-51-985A>T		intron_variant				ENSP00000493895	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 16, 2015

The p.Lys3X variant in EDNRB (NM_001201387.1) has not been previously reported i n individuals with hearing loss, type 4 Waardenburg syndrome, or Hirschsprung di sease, and was absent from large population studies. This nonsense variant affec ts the coding region of only one of four transcript isoforms of the EDNRB gene a nd exon 1 of this isoform lies in either intergenic or intronic regions of the o ther EDNRB isoforms. In addition, pathogenic variants in exon 1 of this transcri pt have not been reported in affected individuals and this exon is enriched for loss of function variants compared with other exons of this gene in the control population (ExAC, http://exac.broadinstitute.org). This suggests that this exon and/or transcript may not be critical for a functional protein; however, additio nal studies are needed to confirm this. In summary, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.42	N
MutationTaster	Benign	1.0	A
Vest4		0.63
GERP RS		4.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876657805; hg19: chr13-78493744;