rs140514830
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_001122659.3(EDNRB):c.758G>A(p.Arg253Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,612,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R253P) has been classified as Uncertain significance.
Frequency
Consequence
NM_001122659.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDNRB | NM_001122659.3 | c.758G>A | p.Arg253Gln | missense_variant | 3/7 | ENST00000646607.2 | |
EDNRB-AS1 | NR_103853.1 | n.1695-4493C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDNRB | ENST00000646607.2 | c.758G>A | p.Arg253Gln | missense_variant | 3/7 | NM_001122659.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000659 AC: 10AN: 151830Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250928Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135628
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1460874Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 726768
GnomAD4 genome ? AF: 0.0000659 AC: 10AN: 151830Hom.: 0 Cov.: 32 AF XY: 0.0000809 AC XY: 6AN XY: 74154
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 03, 2017 | The p.Arg343Gln variant in EDNRB has not been previously reported in individuals with hearing loss, but has been identified in several populations including 5/1 26336 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs140514830). Although this variant has been seen in the general population, its frequency is not high enough to rule out a patho genic role. Computational prediction tools and conservation analysis suggest tha t the p.Arg343Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical signi ficance of the p.Arg343Gln variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 253 of the EDNRB protein (p.Arg253Gln). This variant is present in population databases (rs140514830, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with EDNRB-related conditions. ClinVar contains an entry for this variant (Variation ID: 504854). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EDNRB protein function with a negative predictive value of 80%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at