4-147485937-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001957.4(EDNRA):c.256A>G(p.Ile86Val) variant causes a missense change. The variant allele was found at a frequency of 0.00123 in 1,614,234 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I86M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 17 hom. )

Consequence

EDNRA
NM_001957.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.79

Publications

4 publications found

Variant links:

Genes affected

EDNRA (HGNC:3179): (endothelin receptor type A) This gene encodes the receptor for endothelin-1, a peptide that plays a role in potent and long-lasting vasoconstriction. This receptor associates with guanine-nucleotide-binding (G) proteins, and this coupling activates a phosphatidylinositol-calcium second messenger system. Polymorphisms in this gene have been linked to migraine headache resistance. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

EDNRA Gene-Disease associations (from GenCC):

mandibulofacial dysostosis with alopecia
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
cystic fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EDNRA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058206916).

BP6

Variant 4-147485937-A-G is Benign according to our data. Variant chr4-147485937-A-G is described in ClinVar as Benign. ClinVar VariationId is 1537732.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001957.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDNRA	NM_001957.4	MANE Select	c.256A>G	p.Ile86Val	missense	Exon 2 of 8	NP_001948.1	P25101-1
EDNRA	NM_001166055.2		c.256A>G	p.Ile86Val	missense	Exon 2 of 6	NP_001159527.1	P25101-4
EDNRA	NM_001354797.2		c.256A>G	p.Ile86Val	missense	Exon 2 of 4	NP_001341726.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDNRA	ENST00000651419.1	MANE Select	c.256A>G	p.Ile86Val	missense	Exon 2 of 8	ENSP00000498969.1	P25101-1
EDNRA	ENST00000324300.10	TSL:1	c.256A>G	p.Ile86Val	missense	Exon 2 of 8	ENSP00000315011.5	P25101-1
EDNRA	ENST00000506066.1	TSL:1	c.256A>G	p.Ile86Val	missense	Exon 1 of 5	ENSP00000425281.1	P25101-4

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

351

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00282

AC:

708

AN:

251482

AF XY:

0.00274

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000870

Gnomad FIN exome

AF:

0.0285

Gnomad NFE exome

AF:

0.000519

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00112

AC:

1636

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

793

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000428

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0266

AC:

1419

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000132

AC:

147

AN:

1112008

Other (OTH)

AF:

0.000861

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

120

240

360

480

600

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:

0.00230

AC:

351

AN:

152346

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000966

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0273

AC:

290

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000779

AC:

AN:

68038

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000559

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00196

AC:

238

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.31

Eigen

Benign

-0.22

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0058

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

3.8

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.11

REVEL

Benign

0.059

Sift

Benign

1.0

Sift4G

Benign

0.95

Polyphen

0.0010

Vest4

0.095

MVP

0.37

MPC

0.78

ClinPred

0.036

GERP RS

6.0

PromoterAI

-0.0040

Neutral

(source)

Varity_R

0.069

gMVP

0.48

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over