rs104894388

Positions:

• chr13-77903543-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_001122659.3(EDNRB):​c.548C>G​(p.Ala183Gly) variant causes a missense change involving the alteration of a 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.60

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001122659.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786
• PP5: Variant 13-77903543-G-C is Pathogenic according to our data. Variant chr13-77903543-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 16634.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-77903543-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDNRB	NM_001122659.3	c.548C>G	p.Ala183Gly	missense_variant	2/7	ENST00000646607.2
EDNRB-AS1	NR_103853.1	n.1695-4149G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDNRB	ENST00000646607.2	c.548C>G	p.Ala183Gly	missense_variant	2/7		NM_001122659.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Waardenburg syndrome type 4A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;.;.;.;.;D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.37	T
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.5	N;.;.;N;.;.;.;.;.
REVEL	Uncertain	0.64
Sift	Benign	0.035	D;.;.;D;.;.;.;.;.
Sift4G	Benign	0.11	T;.;.;T;.;T;.;.;.
Polyphen		0.022	B;B;B;B;B;P;B;.;.
Vest4		0.59
MutPred		0.77		.;Loss of ubiquitination at K182 (P = 0.1231);Loss of ubiquitination at K182 (P = 0.1231);Loss of ubiquitination at K182 (P = 0.1231);Loss of ubiquitination at K182 (P = 0.1231);Loss of ubiquitination at K182 (P = 0.1231);Loss of ubiquitination at K182 (P = 0.1231);.;Loss of ubiquitination at K182 (P = 0.1231);
MVP		0.76
MPC		0.57
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.54
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs104894388; hg19: chr13-78477678;