4-147521854-C-T

Variant names:

• chr4-147521854-C-T
• rs908581
• NM_001957.4:c.548+1876C>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.548+1876C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 152,160 control chromosomes in the GnomAD database, including 1,040 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 0.11 (1040 hom., cov: 32)
• Consequence: EDNRA NM_001957.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 1 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRA	NM_001957.4	c.548+1876C>T		intron_variant	Intron 3 of 7	ENST00000651419.1	NP_001948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDNRA	ENST00000651419.1	c.548+1876C>T		intron_variant	Intron 3 of 7		NM_001957.4	ENSP00000498969.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17169 AN: 152044 Hom.: 1043 Cov.: 32

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.108

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

GnomAD4 genome AF: 0.113 AC: 17162 AN: 152160 Hom.: 1040 Cov.: 32 AF XY: 0.116 AC XY: 8659 AN XY: 74392

African (AFR) AF: 0.0910 AC: 3779 AN: 41536

American (AMR) AF: 0.108 AC: 1650 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 458 AN: 3472

East Asian (EAS) AF: 0.192 AC: 996 AN: 5184

South Asian (SAS) AF: 0.254 AC: 1223 AN: 4814

European-Finnish (FIN) AF: 0.119 AC: 1253 AN: 10548

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7456 AN: 68006

Other (OTH) AF: 0.109 AC: 229 AN: 2110

Alfa AF: 0.112 Hom.: 121

Bravo AF: 0.110

Asia WGS AF: 0.223 AC: 773 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.20
DANN	Benign	0.43
PhyloP100		-1.1
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: rs908581; hg19: chr4-148443006;