4-147481217-G-A

Variant names:

• chr4-147481217-G-A
• rs1801708
• NM_001957.4:c.-230G>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.-230G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 152,706 control chromosomes in the GnomAD database, including 20,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.46 (20282 hom., cov: 32)
  • Exomes 𝑓: 0.39 (45 hom.)
• Consequence: EDNRA NM_001957.4 5_prime_UTR
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: 1.56
• Publications: 14 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.834 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.-230G>A		5_prime_UTR	Exon 1 of 8	NP_001948.1
	EDNRA	NR_045958.2		n.121G>A		non_coding_transcript_exon	Exon 1 of 7
	EDNRA	NR_148963.2		n.121G>A		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRA	ENST00000651419.1	MANE Select	c.-230G>A		5_prime_UTR	Exon 1 of 8	ENSP00000498969.1
	EDNRA	ENST00000324300.10	TSL:1	c.-230G>A		5_prime_UTR	Exon 1 of 8	ENSP00000315011.5
	EDNRA	ENST00000358556.8	TSL:5	c.-230G>A		5_prime_UTR	Exon 1 of 6	ENSP00000351359.4

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69175 AN: 151974 Hom.: 20229 Cov.: 32

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.436

GnomAD4 exome AF: 0.390 AC: 240 AN: 616 Hom.: 45 Cov.: 0 AF XY: 0.384 AC XY: 132 AN XY: 344

African (AFR) AF: 0.833 AC: 5 AN: 6

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.333 AC: 4 AN: 12

South Asian (SAS) AF: 0.417 AC: 165 AN: 396

European-Finnish (FIN) AF: 0.500 AC: 3 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.299 AC: 55 AN: 184

Other (OTH) AF: 0.750 AC: 6 AN: 8

GnomAD4 genome AF: 0.456 AC: 69289 AN: 152090 Hom.: 20282 Cov.: 32 AF XY: 0.449 AC XY: 33403 AN XY: 74340

African (AFR) AF: 0.841 AC: 34932 AN: 41512

American (AMR) AF: 0.340 AC: 5199 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1287 AN: 3470

East Asian (EAS) AF: 0.327 AC: 1669 AN: 5104

South Asian (SAS) AF: 0.438 AC: 2107 AN: 4816

European-Finnish (FIN) AF: 0.242 AC: 2560 AN: 10594

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20164 AN: 67982

Other (OTH) AF: 0.435 AC: 918 AN: 2112

Alfa AF: 0.352 Hom.: 14442

Bravo AF: 0.481

Asia WGS AF: 0.439 AC: 1524 AN: 3478

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Migraine, resistance to Benign:1

May 22, 2001

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		1.6
PromoterAI		0.15	Neutral
Mutation Taster		=300/0	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: rs1801708; hg19: chr4-148402369;