Genetic Variant EYA4:c.33+28459T>C (chr6-133303272-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004100.5(EYA4):c.33+28459T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 152,282 control chromosomes in the GnomAD database, including 1,360 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1360 hom., cov: 32)

Consequence

EYA4
NM_004100.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.15

Publications

4 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:

LOC124901403 (HGNC:):

LOC124901403 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA4	NM_004100.5 link	c.33+28459T>C		intron_variant	Intron 2 of 19	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.33+28459T>C		intron_variant	Intron 2 of 19	1	NM_004100.5	ENSP00000347434.7		O95677-1

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18125

AN:

152164

Hom.:

1361

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0309

Gnomad AMI

AF:

0.220

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.120

Gnomad EAS

AF:

0.162

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.129

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.168

Gnomad OTH

AF:

0.105

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.119

AC:

18116

AN:

152282

Hom.:

1360

Cov.:

AF XY:

0.119

AC XY:

8827

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0308

AC:

1282

AN:

41582

American (AMR)

AF:

0.113

AC:

1734

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

416

AN:

3470

East Asian (EAS)

AF:

0.163

AC:

844

AN:

5176

South Asian (SAS)

AF:

0.123

AC:

594

AN:

4832

European-Finnish (FIN)

AF:

0.129

AC:

1369

AN:

10602

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.168

AC:

11442

AN:

68006

Other (OTH)

AF:

0.103

AC:

218

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

791

1582

2373

3164

3955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

214

428

642

856

1070

<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:

0.0816

Hom.:

133

Bravo

AF:

0.113

Asia WGS

AF:

0.128

AC:

447

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

7.7

(source)

DANN

Benign

0.86

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over