6-133274785-A-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_004100.5(EYA4):c.5A>G(p.Glu2Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

EYA4
NM_004100.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.84

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 Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000116 (17/1461414) while in subpopulation MID AF= 0.000174 (1/5762). AF 95% confidence interval is 0.000058. There are 0 homozygotes in gnomad4_exome. There are 9 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA4	NM_004100.5 link	c.5A>G	p.Glu2Gly	missense_variant	Exon 2 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.5A>G	p.Glu2Gly	missense_variant	Exon 2 of 20	1	NM_004100.5	ENSP00000347434.7		O95677-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251282

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461414

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 01, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Dilated cardiomyopathy 1J

Uncertain:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2 of the EYA4 protein (p.Glu2Gly). This variant is present in population databases (rs780081930, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with EYA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 534390). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Jan 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E2G variant (also known as c.5A>G), located in coding exon 1 of the EYA4 gene, results from an A to G substitution at nucleotide position 5. The glutamic acid at codon 2 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.011

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

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.45

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

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.0

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

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.84

N;N;N;N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.0030

D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.035

D;D;D;D;T;D;D;T

Polyphen

0.91, 0.99, 0.97

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

Vest4

0.50

MutPred

0.16

Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);

MVP

0.94

MPC

0.24

ClinPred

0.52

GERP RS

5.7

Varity_R

0.12

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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