chr4-147497403-T-C

Variant names:

• chr4-147497403-T-C
• rs3942348
• NM_001957.4:c.420+11302T>C

Variant summary

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

The NM_001957.4(EDNRA):​c.420+11302T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 152,212 control chromosomes in the GnomAD database, including 238 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 0.031 (238 hom., cov: 31)
• Consequence: EDNRA NM_001957.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.727
• Publications: 0 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRA	NM_001957.4	MANE Select	c.420+11302T>C		intron	N/A	NP_001948.1
	EDNRA	NM_001166055.2		c.420+11302T>C		intron	N/A	NP_001159527.1
	EDNRA	NM_001354797.2		c.420+11302T>C		intron	N/A	NP_001341726.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRA	ENST00000651419.1	MANE Select	c.420+11302T>C		intron	N/A	ENSP00000498969.1
	EDNRA	ENST00000324300.10	TSL:1	c.420+11302T>C		intron	N/A	ENSP00000315011.5
	EDNRA	ENST00000506066.1	TSL:1	c.420+11302T>C		intron	N/A	ENSP00000425281.1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4678 AN: 152094 Hom.: 237 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0299

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0249

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

GnomAD4 genome AF: 0.0308 AC: 4692 AN: 152212 Hom.: 238 Cov.: 31 AF XY: 0.0306 AC XY: 2275 AN XY: 74418

African (AFR) AF: 0.104 AC: 4314 AN: 41494

American (AMR) AF: 0.0101 AC: 155 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0295 AC: 142 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68024

Other (OTH) AF: 0.0246 AC: 52 AN: 2110

Alfa AF: 0.0270 Hom.: 16

Bravo AF: 0.0341

Asia WGS AF: 0.0160 AC: 58 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.6
DANN	Benign	0.72
PhyloP100		0.73
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: rs3942348; hg19: chr4-148418555;