6-133468590-G-A

Position:

chr6-133468590-G-A

Variant summary

Our verdict is Benign. Variant got -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:15

Conservation

PhyloP100: 9.52

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 -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 [Likely_benign]. Clinvar id is 44773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133468590-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
EYA4	NM_004100.5 linkuse as main transcript	c.829G>A	p.Gly277Ser	missense_variant	11/20	ENST00000355286.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA4	ENST00000355286.12 linkuse as main transcript	c.829G>A	p.Gly277Ser	missense_variant	11/20	1	NM_004100.5	P4	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

GnomAD3 exomes

AF:

0.333

AC:

83517

AN:

250774

Hom.:

14517

AF XY:

0.334

AC XY:

45320

AN XY:

135514

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 SAS exome

AF:

0.384

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

Gnomad4 AFR exome

AF:

0.544

Gnomad4 AMR exome

AF:

0.288

Gnomad4 ASJ exome

AF:

0.303

Gnomad4 EAS exome

AF:

0.353

Gnomad4 SAS exome

AF:

0.388

Gnomad4 FIN exome

AF:

0.248

Gnomad4 NFE exome

AF:

0.319

Gnomad4 OTH exome

AF:

0.335

GnomAD4 genome

AF:

0.377

AC:

57173

AN:

151670

Hom.:

11687

Cov.:

AF XY:

0.372

AC XY:

27593

AN XY:

74098

show subpopulations

Gnomad4 AFR

AF:

0.538

Gnomad4 AMR

AF:

0.323

Gnomad4 ASJ

AF:

0.293

Gnomad4 EAS

AF:

0.345

Gnomad4 SAS

AF:

0.406

Gnomad4 FIN

AF:

0.226

Gnomad4 NFE

AF:

0.320

Gnomad4 OTH

AF:

0.367

Alfa

AF:

0.331

Hom.:

21560

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

Dilated cardiomyopathy 1J

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Autosomal dominant nonsyndromic hearing loss 10

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 30, 2022

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2015

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

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;.;.;.

MutationTaster

Benign

4.0e-10

P;P;P;P;P;P;P;P

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

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

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