chr13-77919452-A-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The ENST00000377211.8(EDNRB):c.164T>G(p.Leu55Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,612,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

EDNRB
ENST00000377211.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.38

Publications

0 publications found

Variant links:

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 links:

OBI1-AS1 (HGNC:42700): (OBI1 antisense RNA 1)

OBI1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037023604).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000138 (21/152198) while in subpopulation AFR AF = 0.000506 (21/41514). AF 95% confidence interval is 0.000338. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRB	NM_001201397.2 link	c.164T>G	p.Leu55Arg	missense_variant	Exon 1 of 8		NP_001188326.1	P24530-3A0A024R638
EDNRB	NM_000115.5 link	c.-51-828T>G		intron_variant	Intron 1 of 7		NP_000106.1	P24530-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
EDNRB	ENST00000377211.8 link	c.164T>G	p.Leu55Arg	missense_variant	Exon 1 of 8	1	ENSP00000366416.4	P24530-3
EDNRB	ENST00000643890.1 link	c.-107T>G		5_prime_UTR_variant	Exon 1 of 7		ENSP00000495815.1	A0A2R8Y748
EDNRB	ENST00000646948.1 link	c.-51-828T>G		intron_variant	Intron 1 of 7		ENSP00000493895.1	P24530-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000414

AC:

AN:

241410

AF XY:

0.0000302

show subpopulations

Gnomad AFR exome

AF:

0.000420

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1460424

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726482

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33476

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111738

Other (OTH)

AF:

0.0000166

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000138

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41514

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000151

ExAC

AF:

0.0000259

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 05, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Leu55Arg vari ant in EDNRB has not been previously reported in individuals with hearing loss. This variant has been identified in 2/8470 African chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs761846391). Al though this variant has been seen in the general population, its frequency is no t high enough to rule out a pathogenic role. The Leucine (Leu) at position 55 is not conserved in mammals or evolutionary distant species, raising the possibili ty that a change at this position may be tolerated. Additional computational pre diction tools suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, whil e the clinical significance of the p.Leu55Arg variant is uncertain, these data s uggest that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.17

(source)

DANN

Benign

0.95

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.28

M_CAP

Benign

0.024

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.92

PhyloP100

-1.4

PrimateAI

Benign

0.44

PROVEAN

Benign

0.030

REVEL

Benign

0.088

Sift

Benign

0.26

Polyphen

0.037

Vest4

0.057

MVP

0.23

MPC

0.67

ClinPred

0.070

GERP RS

-4.2

PromoterAI

-0.12

Neutral

(source)

gMVP

0.071

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over