rs10305860

Variant names:

• chr4-147484735-G-A
• rs10305860
• NM_001957.4:c.-70-877G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001957.4(EDNRA):​c.-70-877G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 152,040 control chromosomes in the GnomAD database, including 12,149 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (12149 hom., cov: 33)
• Consequence: EDNRA NM_001957.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.114
• Publications: 3 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRA	NM_001957.4	c.-70-877G>A		intron_variant	Intron 1 of 7	ENST00000651419.1	NP_001948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDNRA	ENST00000651419.1	c.-70-877G>A		intron_variant	Intron 1 of 7		NM_001957.4	ENSP00000498969.1

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57464 AN: 151920 Hom.: 12126 Cov.: 33

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.371

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.378 AC: 57538 AN: 152040 Hom.: 12149 Cov.: 33 AF XY: 0.374 AC XY: 27812 AN XY: 74290

African (AFR) AF: 0.578 AC: 23953 AN: 41466

American (AMR) AF: 0.313 AC: 4777 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1258 AN: 3472

East Asian (EAS) AF: 0.329 AC: 1703 AN: 5176

South Asian (SAS) AF: 0.410 AC: 1974 AN: 4818

European-Finnish (FIN) AF: 0.241 AC: 2540 AN: 10546

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.296 AC: 20102 AN: 67962

Other (OTH) AF: 0.370 AC: 781 AN: 2112

Alfa AF: 0.322 Hom.: 6541

Bravo AF: 0.393

Asia WGS AF: 0.409 AC: 1422 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.8
DANN	Benign	0.61
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs10305860; hg19: chr4-148405887; COSMIC: COSV60098447; COSMIC: COSV60098447;