rs374322196

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004100.5(EYA4):c.9C>T(p.Asp3Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,613,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

EYA4
NM_004100.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.23

Publications

1 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 6-133274789-C-T is Benign according to our data. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133274789-C-T is described in CliVar as Likely_benign. Clinvar id is 227371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.23 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000855 (13/152132) while in subpopulation NFE AF = 0.000162 (11/68028). AF 95% confidence interval is 0.0000905. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA4	NM_004100.5 link	c.9C>T	p.Asp3Asp	synonymous_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.9C>T	p.Asp3Asp	synonymous_variant	Exon 2 of 20	1	NM_004100.5	ENSP00000347434.7		O95677-1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000517

AC:

AN:

251292

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000222

AC:

324

AN:

1461402

Hom.:

Cov.:

AF XY:

0.000221

AC XY:

161

AN XY:

727014

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39620

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000284

AC:

316

AN:

1111720

Other (OTH)

AF:

0.0000994

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.0000855

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.548

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000990

Hom.:

Bravo

AF:

0.000106

Asia WGS

AF:

0.000868

AC:

AN:

3472

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

May 17, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asp3Asp in exon 2 of EYA4: This variant is not expected to have clinical signifi cance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 5/66650 European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs374322196). -

Dilated cardiomyopathy 1J

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 21, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

1.2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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