rs5333

Variant names:

• chr4-147539885-T-C
• rs5333
• NM_001957.4:c.969T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001957.4(EDNRA):​c.969T>C​(p.His323His) 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 1,611,714 control chromosomes in the GnomAD database, including 64,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10478 hom., cov: 31)
  • Exomes 𝑓: 0.26 (54391 hom.)
• Consequence: EDNRA NM_001957.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.474
• Publications: 71 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-147539885-T-C is Benign according to our data. Variant chr4-147539885-T-C is described in ClinVar as Benign. ClinVar VariationId is 1244028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.474 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDNRA	NM_001957.4	c.969T>C	p.His323His	synonymous_variant	Exon 6 of 8	ENST00000651419.1	NP_001948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDNRA	ENST00000651419.1	c.969T>C	p.His323His	synonymous_variant	Exon 6 of 8		NM_001957.4	ENSP00000498969.1

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51655 AN: 151706 Hom.: 10468 Cov.: 31

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.333

GnomAD2 exomes AF: 0.281 AC: 70274 AN: 249922 AF XY: 0.278

Gnomad AFR exome AF: 0.577

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.264 AC: 385461 AN: 1459890 Hom.: 54391 Cov.: 33 AF XY: 0.265 AC XY: 192792 AN XY: 726186

African (AFR) AF: 0.583 AC: 19423 AN: 33342

American (AMR) AF: 0.324 AC: 14374 AN: 44358

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 7966 AN: 26030

East Asian (EAS) AF: 0.234 AC: 9287 AN: 39654

South Asian (SAS) AF: 0.349 AC: 29980 AN: 85878

European-Finnish (FIN) AF: 0.168 AC: 8936 AN: 53338

Middle Eastern (MID) AF: 0.369 AC: 2128 AN: 5760

European-Non Finnish (NFE) AF: 0.249 AC: 276244 AN: 1111232

Other (OTH) AF: 0.284 AC: 17123 AN: 60298

GnomAD4 genome AF: 0.340 AC: 51683 AN: 151824 Hom.: 10478 Cov.: 31 AF XY: 0.335 AC XY: 24869 AN XY: 74202

African (AFR) AF: 0.571 AC: 23592 AN: 41314

American (AMR) AF: 0.301 AC: 4580 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1037 AN: 3470

East Asian (EAS) AF: 0.217 AC: 1125 AN: 5176

South Asian (SAS) AF: 0.335 AC: 1614 AN: 4812

European-Finnish (FIN) AF: 0.177 AC: 1863 AN: 10536

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

European-Non Finnish (NFE) AF: 0.247 AC: 16800 AN: 67972

Other (OTH) AF: 0.330 AC: 695 AN: 2106

Alfa AF: 0.281 Hom.: 10047

Bravo AF: 0.361

Asia WGS AF: 0.300 AC: 1044 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.258

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2021

GeneDx

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

- -

Mandibulofacial dysostosis with alopecia Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.8
DANN	Benign	0.65
PhyloP100		0.47
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: rs5333; hg19: chr4-148461037; COSMIC: COSV60096339;