rs140170914
Positions:
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
Genomes: š 0.00043 ( 0 hom., cov: 32)
Exomes š: 0.00064 ( 1 hom. )
Consequence
EYA4
NM_004100.5 missense
NM_004100.5 missense
Scores
2
9
6
Clinical Significance
Conservation
PhyloP100: 2.11
Genes affected
EYA4 (HGNC:3522): (EYA transcriptional coactivator and phosphatase 4) This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may act as a transcriptional activator through its protein phosphatase activity, and it may be important for eye development, and for continued function of the mature organ of Corti. Mutations in this gene are associated with postlingual, progressive, autosomal dominant hearing loss at the deafness, autosomal dominant non-syndromic sensorineural 10 locus. The encoded protein is also a putative oncogene that mediates DNA repair, apoptosis, and innate immunity following DNA damage, cellular damage, and viral attack. Defects in this gene are also associated with dilated cardiomyopathy 1J. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.23357421).
BP6
?
Variant 6-133481527-G-C is Benign according to our data. Variant chr6-133481527-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192118.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}. Variant chr6-133481527-G-C is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000427 (65/152106) while in subpopulation NFE AF= 0.000853 (58/68020). AF 95% confidence interval is 0.000677. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 65 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYA4 | NM_004100.5 | c.1035G>C | p.Arg345Ser | missense_variant | 12/20 | ENST00000355286.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYA4 | ENST00000355286.12 | c.1035G>C | p.Arg345Ser | missense_variant | 12/20 | 1 | NM_004100.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000427 AC: 65AN: 152106Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000459 AC: 115AN: 250806Hom.: 0 AF XY: 0.000531 AC XY: 72AN XY: 135570
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GnomAD4 exome AF: 0.000640 AC: 936AN: 1461644Hom.: 1 Cov.: 31 AF XY: 0.000666 AC XY: 484AN XY: 727160
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GnomAD4 genome ? AF: 0.000427 AC: 65AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24AN XY: 74276
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 09, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 08, 2015 | 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
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2024 | 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
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D;D;D;D;.;.;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;.;.;D;D
Sift4G
Uncertain
D;D;D;D;.;.;D;D
Polyphen
0.84, 0.13, 0.12, 0.29, 0.43
.;P;B;B;B;B;B;.
Vest4
MutPred
0.32
.;.;.;.;.;.;Gain of phosphorylation at R351 (P = 0.0042);.;
MVP
MPC
0.37
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at