4-147516402-C-T

Variant names:

• chr4-147516402-C-T
• rs1517135
• NM_001957.4:c.421-3449C>T

Variant summary

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

The NM_001957.4(EDNRA):​c.421-3449C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0799 in 152,268 control chromosomes in the GnomAD database, including 1,580 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 0.080 (1580 hom., cov: 32)
• Consequence: EDNRA NM_001957.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.216
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRA	NM_001957.4	c.421-3449C>T		intron_variant	Intron 2 of 7	ENST00000651419.1	NP_001948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDNRA	ENST00000651419.1	c.421-3449C>T		intron_variant	Intron 2 of 7		NM_001957.4	ENSP00000498969.1

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12137 AN: 152152 Hom.: 1572 Cov.: 32

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0324

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0722

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

GnomAD4 genome AF: 0.0799 AC: 12168 AN: 152268 Hom.: 1580 Cov.: 32 AF XY: 0.0769 AC XY: 5728 AN XY: 74448

African (AFR) AF: 0.273 AC: 11327 AN: 41522

American (AMR) AF: 0.0322 AC: 493 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68034

Other (OTH) AF: 0.0715 AC: 151 AN: 2112

Alfa AF: 0.0374 Hom.: 193

Bravo AF: 0.0899

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.7
DANN	Benign	0.61
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1517135; hg19: chr4-148437554;