chr6-133468590-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004100.5(EYA4):c.829G>A(p.Gly277Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,609,232 control chromosomes in the GnomAD database, including 91,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G277D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.38 ( 11687 hom., cov: 31)

Exomes 𝑓: 0.33 ( 79579 hom. )

Consequence

EYA4
NM_004100.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 9.52

Publications

62 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 10
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy 1J
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen

EYA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013802946).

BP6

Variant 6-133468590-G-A is Benign according to our data. Variant chr6-133468590-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA4	NM_004100.5 link	c.829G>A	p.Gly277Ser	missense_variant	Exon 11 of 20	ENST00000355286.12	NP_004091.3	O95677-1Q96CJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12 link	c.829G>A	p.Gly277Ser	missense_variant	Exon 11 of 20	1	NM_004100.5	ENSP00000347434.7		O95677-1

Frequencies

GnomAD3 genomes

AF:

0.377

AC:

57117

AN:

151550

Hom.:

11671

Cov.:

show subpopulations

Gnomad AFR

AF:

0.539

Gnomad AMI

AF:

0.301

Gnomad AMR

AF:

0.323

Gnomad ASJ

AF:

0.293

Gnomad EAS

AF:

0.345

Gnomad SAS

AF:

0.405

Gnomad FIN

AF:

0.226

Gnomad MID

AF:

0.383

Gnomad NFE

AF:

0.320

Gnomad OTH

AF:

0.369

GnomAD2 exomes

AF:

0.333

AC:

83517

AN:

250774

AF XY:

0.334

show subpopulations

Gnomad AFR exome

AF:

0.538

Gnomad AMR exome

AF:

0.281

Gnomad ASJ exome

AF:

0.298

Gnomad EAS exome

AF:

0.353

Gnomad FIN exome

AF:

0.243

Gnomad NFE exome

AF:

0.323

Gnomad OTH exome

AF:

0.330

GnomAD4 exome

AF:

0.326

AC:

475819

AN:

1457562

Hom.:

79579

Cov.:

AF XY:

0.328

AC XY:

237952

AN XY:

725380

show subpopulations

African (AFR)

AF:

0.544

AC:

18153

AN:

33342

American (AMR)

AF:

0.288

AC:

12829

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

7887

AN:

26070

East Asian (EAS)

AF:

0.353

AC:

13989

AN:

39662

South Asian (SAS)

AF:

0.388

AC:

33416

AN:

86168

European-Finnish (FIN)

AF:

0.248

AC:

13220

AN:

53382

Middle Eastern (MID)

AF:

0.395

AC:

2275

AN:

5754

European-Non Finnish (NFE)

AF:

0.319

AC:

353902

AN:

1108370

Other (OTH)

AF:

0.335

AC:

20148

AN:

60212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

15682

31364

47047

62729

78411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11628

23256

34884

46512

58140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.377

AC:

57173

AN:

151670

Hom.:

11687

Cov.:

AF XY:

0.372

AC XY:

27593

AN XY:

74098

show subpopulations

African (AFR)

AF:

0.538

AC:

22264

AN:

41350

American (AMR)

AF:

0.323

AC:

4900

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.293

AC:

1016

AN:

3464

East Asian (EAS)

AF:

0.345

AC:

1774

AN:

5146

South Asian (SAS)

AF:

0.406

AC:

1950

AN:

4802

European-Finnish (FIN)

AF:

0.226

AC:

2384

AN:

10560

Middle Eastern (MID)

AF:

0.388

AC:

114

AN:

294

European-Non Finnish (NFE)

AF:

0.320

AC:

21725

AN:

67850

Other (OTH)

AF:

0.367

AC:

772

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1717

3434

5150

6867

8584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

544

1088

1632

2176

2720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.338

Hom.:

44415

Bravo

AF:

0.388

TwinsUK

AF:

0.306

AC:

1136

ALSPAC

AF:

0.328

AC:

1263

ESP6500AA

AF:

0.520

AC:

2291

ESP6500EA

AF:

0.313

AC:

2690

ExAC

AF:

0.341

AC:

41411

Asia WGS

AF:

0.357

AC:

1241

AN:

3478

EpiCase

AF:

0.325

EpiControl

AF:

0.333

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gly277Ser in Exon 11 of EYA4: This variant is not expected to have clinical sign ificance because it has been identified in 48.2% (1802/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs9493627). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 11, 2020

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1J

Benign:3

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 10

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal dominant nonsyndromic hearing loss 10;C1854368:Dilated cardiomyopathy 1J

Benign:1

Mar 30, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Jun 19, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

.;T;T;.;T;.;T;T

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;.;D;D;D;D;D

MetaRNN

Benign

0.0014

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.9

.;.;M;M;M;.;.;.

PhyloP100

9.5

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.9

N;N;N;N;.;.;N;N

REVEL

Uncertain

0.42

Sift

Benign

0.18

T;T;T;T;.;.;T;T

Sift4G

Benign

0.25

T;T;T;T;.;.;T;T

Polyphen

0.97, 0.97, 0.86

.;D;D;D;D;P;D;.

Vest4

0.43

MPC

0.63

ClinPred

0.023

GERP RS

5.5

Varity_R

0.27

gMVP

0.67

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over