4-147485925-A-C

Position:

• chr4-147485925-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001957.4(EDNRA):​c.244A>C​(p.Ile82Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EDNRA NM_001957.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.87

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EDNRA. . Gene score misZ 2.8025 (greater than the threshold 3.09). Trascript score misZ 3.9779 (greater than threshold 3.09). GenCC has associacion of gene with mandibulofacial dysostosis with alopecia.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDNRA	NM_001957.4	c.244A>C	p.Ile82Leu	missense_variant	2/8	ENST00000651419.1	NP_001948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDNRA	ENST00000651419.1	c.244A>C	p.Ile82Leu	missense_variant	2/8		NM_001957.4	ENSP00000498969	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 01, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with EDNRA-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with leucine at codon 82 of the EDNRA protein (p.Ile82Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;.
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.1	L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0050	D;T;T
Sift4G	Benign	0.067	T;T;T
Polyphen		0.87	P;D;D
Vest4		0.67
MutPred		0.60		Loss of ubiquitination at K80 (P = 0.1564);Loss of ubiquitination at K80 (P = 0.1564);Loss of ubiquitination at K80 (P = 0.1564);
MVP		0.62
MPC		1.2
ClinPred		0.86	D
GERP RS		6.0
Varity_R		0.46
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-148407077;