rs773095472
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_004100.5(EYA4):c.978C>G(p.Phe326Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,400 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_004100.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151960Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000400 AC: 10AN: 250036Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135224
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461440Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727046
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151960Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74196
ClinVar
Submissions by phenotype
not provided Uncertain:2
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In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25681523, 30245029, 23990876, 30165862) -
Dilated cardiomyopathy 1J Uncertain:2
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 326 of the EYA4 protein (p.Phe326Leu). This variant is present in population databases (rs773095472, gnomAD 0.06%). This missense change has been observed in individual(s) with familial nonsyndromic hearing loss and dilated cardiomyopathy (PMID: 23990876, 30165862). This variant is also known as c.909C>G; p.Phe303Leu. ClinVar contains an entry for this variant (Variation ID: 191663). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt EYA4 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. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Autosomal dominant nonsyndromic hearing loss 10;C1854368:Dilated cardiomyopathy 1J Uncertain:1
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Autosomal dominant nonsyndromic hearing loss 10 Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Cardiovascular phenotype Uncertain:1
The p.F326L variant (also known as c.978C>G), located in coding exon 11 of the EYA4 gene, results from a C to G substitution at nucleotide position 978. The phenylalanine at codon 326 is replaced by leucine, an amino acid with highly similar properties. This alteration (also referred to as p.F303L) has been reported in non-syndromic hearing loss and cardiomyopathy cohorts (Choi BY et al. PLoS One, 2013 Aug;8:e68692; Kim YR et al. PLoS One, 2015 Mar;10:e0119443; Lu C et al. J Transl Med, 2018 08;16:241). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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