chr13-77898244-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_001122659.3(EDNRB):c.1285G>A(p.Gly429Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00014 in 1,611,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001122659.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000198 AC: 30AN: 151896Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000124 AC: 31AN: 249884Hom.: 0 AF XY: 0.000126 AC XY: 17AN XY: 135088
GnomAD4 exome AF: 0.000134 AC: 195AN: 1459948Hom.: 0 Cov.: 31 AF XY: 0.000138 AC XY: 100AN XY: 726268
GnomAD4 genome AF: 0.000197 AC: 30AN: 152014Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74308
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant summary: EDNRB c.1285G>A (p.Gly429Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 275528 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1285G>A in individuals affected with Waardenburg syndrome type 4A and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
The p.Gly519Arg variant in EDNRB has not been previously reported in individuals with hearing loss or Waardenburg syndrome, but has been identified in 6/65674 E uropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs144565124). Although this variant has been seen in the ge neral population, its frequency is not high enough to rule out a pathogenic role . Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical signi ficance of the Gly519Arg variant is uncertain. -
Inborn genetic diseases Uncertain:1
The c.1285G>A (p.G429R) alteration is located in exon 8 (coding exon 7) of the EDNRB gene. This alteration results from a G to A substitution at nucleotide position 1285, causing the glycine (G) at amino acid position 429 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Hirschsprung Disease, Recessive Uncertain:1
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not provided Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 429 of the EDNRB protein (p.Gly429Arg). This variant is present in population databases (rs144565124, gnomAD 0.05%). 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: 228662). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
ABCD syndrome;C1838564:Hirschsprung disease, susceptibility to, 2;C1848519:Waardenburg syndrome type 4A Uncertain:1
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Waardenburg syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at