chr6-133462487-ATCT-A

Variant names:

• chr6-133462487-ATCT-A
• rs139659489
• NM_004100.5:c.580+14_580+16delTCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004100.5(EYA4):​c.580+14_580+16delTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,946 control chromosomes in the GnomAD database, including 725 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (240 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (485 hom.)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.18

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 6-133462487-ATCT-A is Benign according to our data. Variant chr6-133462487-ATCT-A is described in ClinVar as [Likely_benign]. Clinvar id is 178670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133462487-ATCT-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA4	NM_004100.5	c.580+14_580+16delTCT		intron_variant	Intron 8 of 19	ENST00000355286.12	NP_004091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12	c.580+14_580+16delTCT		intron_variant	Intron 8 of 19	1	NM_004100.5	ENSP00000347434.7

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 5090 AN: 152138 Hom.: 238 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0789

Gnomad SAS AF: 0.0441

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0198 AC: 4961 AN: 251064 Hom.: 212 AF XY: 0.0195 AC XY: 2642 AN XY: 135674

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.00542

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0912

Gnomad SAS exome AF: 0.0422

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000617

Gnomad OTH exome AF: 0.00833

GnomAD4 exome AF: 0.00825 AC: 12054 AN: 1461690 Hom.: 485 AF XY: 0.00916 AC XY: 6663 AN XY: 727144

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.00631

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0829

Gnomad4 SAS exome AF: 0.0426

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000352

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0335 AC: 5096 AN: 152256 Hom.: 240 Cov.: 32 AF XY: 0.0339 AC XY: 2526 AN XY: 74436

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0785

Gnomad4 SAS AF: 0.0437

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0147 Hom.: 18

Bravo AF: 0.0374

Asia WGS AF: 0.0420 AC: 144 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 21, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.580+14_580+16delTCT in intron 8 of EYA4: This variant is not expected to have clinical significance because it has been identified in 10.3% (53/1072) of Afric an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs139659489) -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: EYA4 c.580+14_580+16delTCT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.02 in 251064 control chromosomes, predominantly at a frequency of 0.1 within the African or African-American subpopulation in the gnomAD database, including 90 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4000-folds over the estimated maximal expected allele frequency for a pathogenic variant in EYA4 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Co-occurrence with another likely pathogenic TTN variant (c.34782_34785delTTGT, p.C11595fsX9) has been reported in an internal sample, providing supporting evidence for a benign role. Two ClinVar submissions (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

Nonsyndromic Hearing Loss, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated Cardiomyopathy, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1J Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 17, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs139659489; hg19: chr6-133783625;