rs143936434
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_004100.5(EYA4):c.1109G>A(p.Arg370His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,611,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R370C) has been classified as Uncertain significance.
Frequency
Consequence
NM_004100.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYA4 | NM_004100.5 | c.1109G>A | p.Arg370His | missense_variant, splice_region_variant | 13/20 | ENST00000355286.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYA4 | ENST00000355286.12 | c.1109G>A | p.Arg370His | missense_variant, splice_region_variant | 13/20 | 1 | NM_004100.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152068Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251092Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135718
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1459656Hom.: 0 Cov.: 29 AF XY: 0.0000344 AC XY: 25AN XY: 726250
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74264
ClinVar
Submissions by phenotype
Autosomal dominant nonsyndromic hearing loss 10 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Santos-Cortez Lab, University of Colorado School of Medicine | Jan 17, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 30, 2015 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Dilated cardiomyopathy 1J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 370 of the EYA4 protein (p.Arg370His). This variant is present in population databases (rs143936434, gnomAD 0.007%). This missense change has been observed in individual(s) with hearing loss (PMID: 30828794). ClinVar contains an entry for this variant (Variation ID: 163451). 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. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2019 | The p.R370H variant (also known as c.1109G>A), located in coding exon 12 of the EYA4 gene, results from a G to A substitution at nucleotide position 1109. The arginine at codon 370 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at