4-147519932-TC-CT

Variant names:

• chr4-147519932-TC-CT
• NM_001957.4:c.502_503delTCinsCT
• EDNRA p.Ser168Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001957.4(EDNRA):​c.502_503delTCinsCT​(p.Ser168Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S168S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDNRA NM_001957.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.45
• Publications: 0 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, G2P, Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRA	NM_001957.4	MANE Select	c.502_503delTCinsCT	p.Ser168Leu	missense	N/A	NP_001948.1	P25101-1
	EDNRA	NM_001354797.2		c.502_503delTCinsCT	p.Ser168Leu	missense	N/A	NP_001341726.1
	EDNRA	NM_001166055.2		c.421-15945_421-15944delTCinsCT		intron	N/A	NP_001159527.1	P25101-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRA	ENST00000651419.1	MANE Select	c.502_503delTCinsCT	p.Ser168Leu	missense	N/A	ENSP00000498969.1	P25101-1
	EDNRA	ENST00000324300.10	TSL:1	c.502_503delTCinsCT	p.Ser168Leu	missense	N/A	ENSP00000315011.5	P25101-1
	EDNRA	ENST00000506066.1	TSL:1	c.421-15945_421-15944delTCinsCT		intron	N/A	ENSP00000425281.1	P25101-4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-148441084;