rs121909196
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000503.6(EYA1):c.1319G>A(p.Arg440Gln) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R440W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000503.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYA1 | NM_000503.6 | c.1319G>A | p.Arg440Gln | missense_variant | 14/18 | ENST00000340726.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYA1 | ENST00000340726.8 | c.1319G>A | p.Arg440Gln | missense_variant | 14/18 | 1 | NM_000503.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Branchiootic syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 02, 2022 | - - |
Branchiooculofacial syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Jan 17, 2019 | - - |
Melnick-Fraser syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 440 of the EYA1 protein (p.Arg440Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with branchiootorenal syndrome (PMID: 10464653, 15146463, 18220287, 21280147, 28832562). This variant is also known as c.1220G>A (p.Arg407Gln). ClinVar contains an entry for this variant (Variation ID: 7935). 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 EYA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EYA1 function (PMID: 19951260, 24489909). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Branchiootorenal syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1997 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 19, 2011 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at