4-147542480-A-G

Variant names:

• chr4-147542480-A-G
• rs141331809
• NM_001957.4:c.1146A>G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001957.4(EDNRA):​c.1146A>G​(p.Ser382Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,614,094 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (30 hom.)
• Consequence: EDNRA NM_001957.4 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.326

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 4-147542480-A-G is Benign according to our data. Variant chr4-147542480-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 711201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.326 with no splicing effect.
• BS2: High AC in GnomAd4 at 569 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRA	NM_001957.4	c.1146A>G	p.Ser382Ser	splice_region_variant, synonymous_variant	Exon 8 of 8	ENST00000651419.1	NP_001948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDNRA	ENST00000651419.1	c.1146A>G	p.Ser382Ser	splice_region_variant, synonymous_variant	Exon 8 of 8		NM_001957.4	ENSP00000498969.1

Frequencies

GnomAD3 genomes AF: 0.00374 AC: 569 AN: 152154 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00539

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00396 AC: 994 AN: 251192 Hom.: 6 AF XY: 0.00402 AC XY: 546 AN XY: 135752

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00347

Gnomad NFE exome AF: 0.00639

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00559 AC: 8169 AN: 1461822 Hom.: 30 Cov.: 31 AF XY: 0.00538 AC XY: 3913 AN XY: 727220

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.00374

Gnomad4 NFE exome AF: 0.00663

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.00374 AC: 569 AN: 152272 Hom.: 3 Cov.: 32 AF XY: 0.00347 AC XY: 258 AN XY: 74450

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00500

Gnomad4 NFE AF: 0.00539

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00483 Hom.: 2

Bravo AF: 0.00371

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00539

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EDNRA: BP4, BP7 -

Migraine with or without aura, susceptibility to, 1;C4225349:Mandibulofacial dysostosis with alopecia Benign:1

Jul 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EDNRA-related disorder Benign:1

Feb 24, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.96
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs141331809; hg19: chr4-148463632;