rs1555290659

Positions:

• chr13-77903541-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001122659.3(EDNRB):​c.550T>C​(p.Ser184Pro) variant causes a missense change. 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S184S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.96

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 8 ACMG points.

• PM1: In a transmembrane_region Helical; Name=3 (size 21) in uniprot entity EDNRB_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001122659.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 13-77903541-A-G is Pathogenic according to our data. Variant chr13-77903541-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547294.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDNRB	NM_001122659.3	c.550T>C	p.Ser184Pro	missense_variant	2/7	ENST00000646607.2	NP_001116131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDNRB	ENST00000646607.2	c.550T>C	p.Ser184Pro	missense_variant	2/7		NM_001122659.3	ENSP00000493527.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Waardenburg syndrome type 4A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;D;D;D;.;D;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;.;.;.;.;D;D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Pathogenic	4.0	.;H;H;H;H;H;H;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.1	D;.;.;D;.;.;.;.;.
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;.;.;D;.;D;.;.;.
Polyphen		1.0	D;D;D;D;D;D;D;.;.
Vest4		0.97
MutPred		0.80		.;Gain of methylation at K182 (P = 0.0718);Gain of methylation at K182 (P = 0.0718);Gain of methylation at K182 (P = 0.0718);Gain of methylation at K182 (P = 0.0718);Gain of methylation at K182 (P = 0.0718);Gain of methylation at K182 (P = 0.0718);.;Gain of methylation at K182 (P = 0.0718);
MVP		0.76
MPC		1.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.98

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: rs1555290659; hg19: chr13-78477676;