chr13-77903199-C-G

Variant names:

• chr13-77903199-C-G
• rs140514830
• NM_001122659.3:c.758G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001122659.3(EDNRB):​c.758G>C​(p.Arg253Pro) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R253Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDNRB NM_001122659.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.73
• Publications: 0 publications found

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:49045): (EDNRB antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122659.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	NM_001122659.3	MANE Select	c.758G>C	p.Arg253Pro	missense	Exon 3 of 7	NP_001116131.1	P24530-1
	EDNRB	NM_001201397.2		c.1028G>C	p.Arg343Pro	missense	Exon 4 of 8	NP_001188326.1	P24530-3
	EDNRB	NM_000115.5		c.758G>C	p.Arg253Pro	missense	Exon 4 of 8	NP_000106.1	P24530-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRB	ENST00000646607.2	MANE Select	c.758G>C	p.Arg253Pro	missense	Exon 3 of 7	ENSP00000493527.1	P24530-1
	EDNRB	ENST00000377211.8	TSL:1	c.1028G>C	p.Arg343Pro	missense	Exon 4 of 8	ENSP00000366416.4	P24530-3
	EDNRB	ENST00000626030.1	TSL:1	c.758G>C	p.Arg253Pro	missense	Exon 3 of 7	ENSP00000486202.1	P24530-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.9	M
PhyloP100		4.7
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.69
Sift	Benign	0.041	D
Sift4G	Uncertain	0.018	D
Polyphen		0.92	P
Vest4		0.84
MutPred		0.63		Loss of catalytic residue at R253 (P = 0.0179)
MVP		0.94
MPC		0.79
ClinPred		0.97	D
GERP RS		3.9
PromoterAI		-0.010	Neutral
Varity_R		0.86
gMVP		0.98
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs140514830; hg19: chr13-78477334;