rs141300030
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_004100.5(EYA4):c.1329G>A(p.Gly443=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,613,358 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000056 ( 0 hom. )
Consequence
EYA4
NM_004100.5 synonymous
NM_004100.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.121
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 -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.58).
BP6
?
Variant 6-133512768-G-A is Benign according to our data. Variant chr6-133512768-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=0.121 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000584 (89/152300) while in subpopulation AFR AF= 0.00202 (84/41576). AF 95% confidence interval is 0.00167. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 89 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYA4 | NM_004100.5 | c.1329G>A | p.Gly443= | synonymous_variant | 15/20 | ENST00000355286.12 | |
TARID | NR_109982.1 | n.2286-5447C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYA4 | ENST00000355286.12 | c.1329G>A | p.Gly443= | synonymous_variant | 15/20 | 1 | NM_004100.5 | P4 | |
TARID | ENST00000607033.5 | n.2262-5447C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000578 AC: 88AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000143 AC: 36AN: 251394Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135864
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GnomAD4 exome AF: 0.0000561 AC: 82AN: 1461058Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30AN XY: 726894
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GnomAD4 genome ? AF: 0.000584 AC: 89AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43AN XY: 74460
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
EYA4-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 11, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2021 | - - |
Dilated cardiomyopathy 1J Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 02, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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