6-133446649-C-T

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

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.10
Variant links:
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

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EYA4NM_004100.5 linkc.103C>T p.Leu35Leu synonymous_variant 4/20 ENST00000355286.12 NP_004091.3 O95677-1Q96CJ7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EYA4ENST00000355286.12 linkc.103C>T p.Leu35Leu synonymous_variant 4/201 NM_004100.5 ENSP00000347434.7 O95677-1

Frequencies

GnomAD3 genomes
AF:
0.00688
AC:
1047
AN:
152142
Hom.:
9
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0231
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00412
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00718
GnomAD3 exomes
AF:
0.00190
AC:
478
AN:
251396
Hom.:
6
AF XY:
0.00147
AC XY:
200
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.0242
Gnomad AMR exome
AF:
0.00182
Gnomad ASJ exome
AF:
0.000595
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000616
Gnomad OTH exome
AF:
0.00114
GnomAD4 exome
AF:
0.000703
AC:
1028
AN:
1461486
Hom.:
16
Cov.:
31
AF XY:
0.000582
AC XY:
423
AN XY:
727062
show subpopulations
Gnomad4 AFR exome
AF:
0.0218
Gnomad4 AMR exome
AF:
0.00203
Gnomad4 ASJ exome
AF:
0.000498
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000693
Gnomad4 OTH exome
AF:
0.00180
GnomAD4 genome
AF:
0.00697
AC:
1062
AN:
152260
Hom.:
9
Cov.:
32
AF XY:
0.00715
AC XY:
532
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.0234
Gnomad4 AMR
AF:
0.00412
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00710
Alfa
AF:
0.000602
Hom.:
0
Bravo
AF:
0.00798
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.000327
EpiControl
AF:
0.0000593

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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesApr 10, 2020- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 29, 2018- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 07, 2012Leu35Leu 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 09, 2020- -
Dilated cardiomyopathy 1J Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 09, 2017This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Autosomal dominant nonsyndromic hearing loss 10 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 09, 2017This 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.31
CADD
Benign
10
DANN
Benign
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35562371; hg19: chr6-133767787; API