rs5334

Variant names:

• chr4-147539921-G-A
• rs5334
• NM_001957.4:c.1005G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001957.4(EDNRA):​c.1005G>A​(p.Glu335Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,608,528 control chromosomes in the GnomAD database, including 64,432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10502 hom., cov: 31)
  • Exomes 𝑓: 0.26 (53930 hom.)
• Consequence: EDNRA NM_001957.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.41
• Publications: 34 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]

TMEM184C-DT (HGNC:55544): (TMEM184C divergent transcript)

LOC124900795 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 4-147539921-G-A is Benign according to our data. Variant chr4-147539921-G-A is described in ClinVar as Benign. ClinVar VariationId is 1255371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 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.1005G>A	p.Glu335Glu	synonymous	Exon 6 of 8	NP_001948.1
	EDNRA	NM_001166055.2		c.678G>A	p.Glu226Glu	synonymous	Exon 4 of 6	NP_001159527.1
	EDNRA	NR_045958.2		n.1156G>A		non_coding_transcript_exon	Exon 5 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRA	ENST00000651419.1	MANE Select	c.1005G>A	p.Glu335Glu	synonymous	Exon 6 of 8	ENSP00000498969.1
	EDNRA	ENST00000324300.10	TSL:1	c.1005G>A	p.Glu335Glu	synonymous	Exon 6 of 8	ENSP00000315011.5
	EDNRA	ENST00000506066.1	TSL:1	c.678G>A	p.Glu226Glu	synonymous	Exon 3 of 5	ENSP00000425281.1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51704 AN: 151758 Hom.: 10492 Cov.: 31

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.334

GnomAD2 exomes AF: 0.278 AC: 68835 AN: 247346 AF XY: 0.276

Gnomad AFR exome AF: 0.576

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.199

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.263 AC: 383536 AN: 1456652 Hom.: 53930 Cov.: 33 AF XY: 0.265 AC XY: 191797 AN XY: 724456

African (AFR) AF: 0.581 AC: 19195 AN: 33052

American (AMR) AF: 0.318 AC: 13869 AN: 43546

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 7892 AN: 25912

East Asian (EAS) AF: 0.234 AC: 9275 AN: 39634

South Asian (SAS) AF: 0.347 AC: 29450 AN: 84954

European-Finnish (FIN) AF: 0.167 AC: 8924 AN: 53310

Middle Eastern (MID) AF: 0.369 AC: 2116 AN: 5736

European-Non Finnish (NFE) AF: 0.248 AC: 275776 AN: 1110362

Other (OTH) AF: 0.283 AC: 17039 AN: 60146

GnomAD4 genome AF: 0.341 AC: 51732 AN: 151876 Hom.: 10502 Cov.: 31 AF XY: 0.335 AC XY: 24898 AN XY: 74224

African (AFR) AF: 0.571 AC: 23637 AN: 41380

American (AMR) AF: 0.301 AC: 4591 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1038 AN: 3470

East Asian (EAS) AF: 0.217 AC: 1119 AN: 5162

South Asian (SAS) AF: 0.334 AC: 1608 AN: 4812

European-Finnish (FIN) AF: 0.177 AC: 1862 AN: 10516

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.247 AC: 16799 AN: 67962

Other (OTH) AF: 0.331 AC: 699 AN: 2110

Alfa AF: 0.280 Hom.: 30555

Bravo AF: 0.361

Asia WGS AF: 0.300 AC: 1044 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Mandibulofacial dysostosis with alopecia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.2
DANN	Benign	0.48
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs5334; hg19: chr4-148461073; COSMIC: COSV60096347;