6-133446649-C-T
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_004100.5(EYA4):c.103C>T(p.Leu35Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,613,746 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0070 ( 9 hom., cov: 32)
Exomes 𝑓: 0.00070 ( 16 hom. )
Consequence
EYA4
NM_004100.5 synonymous
NM_004100.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.10
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 -19 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.31).
BP6
Variant 6-133446649-C-T is Benign according to our data. Variant chr6-133446649-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=3.1 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00697 (1062/152260) while in subpopulation AFR AF= 0.0234 (973/41552). AF 95% confidence interval is 0.0222. There are 9 homozygotes in gnomad4. There are 532 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1062 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00688 AC: 1047AN: 152142Hom.: 9 Cov.: 32
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GnomAD3 exomes AF: 0.00190 AC: 478AN: 251396Hom.: 6 AF XY: 0.00147 AC XY: 200AN XY: 135864
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GnomAD4 exome AF: 0.000703 AC: 1028AN: 1461486Hom.: 16 Cov.: 31 AF XY: 0.000582 AC XY: 423AN XY: 727062
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GnomAD4 genome AF: 0.00697 AC: 1062AN: 152260Hom.: 9 Cov.: 32 AF XY: 0.00715 AC XY: 532AN XY: 74444
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 10, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2018 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2012 | Leu35Leu in Exon 04 of EYA4: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 2.1% (80/3738) of Afri can American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs35562371). - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 09, 2020 | - - |
Dilated cardiomyopathy 1J Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 09, 2017 | 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Autosomal dominant nonsyndromic hearing loss 10 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 09, 2017 | 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at