6-133481527-G-C
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_004100.5(EYA4):āc.1035G>Cā(p.Arg345Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00062 in 1,613,750 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004100.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000427 AC: 65AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000459 AC: 115AN: 250806Hom.: 0 AF XY: 0.000531 AC XY: 72AN XY: 135570
GnomAD4 exome AF: 0.000640 AC: 936AN: 1461644Hom.: 1 Cov.: 31 AF XY: 0.000666 AC XY: 484AN XY: 727160
GnomAD4 genome AF: 0.000427 AC: 65AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24AN XY: 74276
ClinVar
Submissions by phenotype
not provided Benign:4
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not specified Uncertain:1Benign:1
Variant summary: EYA4 c.1035G>C (p.Arg345Ser) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 250806 control chromosomes, predominantly at a frequency of 0.00095 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 61-fold of the estimated maximal expected allele frequency for a pathogenic variant in EYA4 causing Dilated Cardiomyopathy phenotype (1.6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1035G>C has been reported in the literature in individuals from studies evaluating auditory and cardiovascular phenotypes (Ng_2013, Sommen_2016, Ahmadmehrabi_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=2) and as VUS (n=3) . Based on the evidence outlined above, the variant was classified as likely benign. -
Variant classified as Uncertain Significance - Favor Benign. The p.Arg345Ser var iant in EYA4 has not been previously reported in individuals with hearing loss a nd has been identified in 0.1% (71/66610) of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140170914). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg345Ser variant is uncertain, frequency data suggest tha t it is more likely to be benign. -
Dilated cardiomyopathy 1J Uncertain:1Benign:1
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Cardiovascular phenotype Uncertain:1
The p.R345S variant (also known as c.1035G>C), located in coding exon 11 of the EYA4 gene, results from a G to C substitution at nucleotide position 1035. The arginine at codon 345 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet. 2013;6:337-46). This variant was also reported in a hearing loss cohort (Sommen M et al. Hum Mutat, 2016 Aug;37:812-9). 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. -
Autosomal dominant nonsyndromic hearing loss 10 Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at