4-147486067-A-T

Variant names:

• chr4-147486067-A-T
• rs786205230
• NM_001957.4:c.386A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001957.4(EDNRA):​c.386A>T​(p.Tyr129Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y129C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EDNRA NM_001957.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.76
• Publications: 8 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774
• PP5: Variant 4-147486067-A-T is Pathogenic according to our data. Variant chr4-147486067-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 190323.Status of the report is no_assertion_criteria_provided, 0 stars.

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.386A>T	p.Tyr129Phe	missense	Exon 2 of 8	NP_001948.1
	EDNRA	NM_001166055.2		c.386A>T	p.Tyr129Phe	missense	Exon 2 of 6	NP_001159527.1
	EDNRA	NM_001354797.2		c.386A>T	p.Tyr129Phe	missense	Exon 2 of 4	NP_001341726.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDNRA	ENST00000651419.1	MANE Select	c.386A>T	p.Tyr129Phe	missense	Exon 2 of 8	ENSP00000498969.1
	EDNRA	ENST00000324300.10	TSL:1	c.386A>T	p.Tyr129Phe	missense	Exon 2 of 8	ENSP00000315011.5
	EDNRA	ENST00000506066.1	TSL:1	c.386A>T	p.Tyr129Phe	missense	Exon 1 of 5	ENSP00000425281.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mandibulofacial dysostosis with alopecia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.2	L
PhyloP100		8.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.74
Sift	Benign	0.10	T
Sift4G	Uncertain	0.060	T
Polyphen		0.36	B
Vest4		0.81
MutPred		0.33		Loss of catalytic residue at I128 (P = 0.1558)
MVP		0.74
MPC		1.8
ClinPred		0.97	D
GERP RS		5.7
PromoterAI		0.0091	Neutral
Varity_R		0.60
gMVP		0.79
Mutation Taster		=14/86	disease causing (ClinVar)

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: rs786205230; hg19: chr4-148407219;