rs139659489

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004100.5(EYA4):c.580+14_580+16del 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

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.18

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]

EYA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
EYA4	NM_004100.5 linkuse as main transcript	c.580+14_580+16del		intron_variant		ENST00000355286.12	NP_004091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12 linkuse as main transcript	c.580+14_580+16del		intron_variant		1	NM_004100.5	ENSP00000347434	P4	O95677-1

Frequencies

GnomAD3 genomes

AF:

0.0335

AC:

5090

AN:

152138

Hom.:

238

Cov.:

show subpopulations

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

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0339

AC XY:

2526

AN XY:

74436

show subpopulations

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.:

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

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 21, 2015	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) -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2019	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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2020

- -

Dilated cardiomyopathy 1J

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over