Genetic Variant EYA4:p.Val432Phe (chr6-133512733-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004100.5(EYA4):c.1294G>T(p.Val432Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V432L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

EYA4
NM_004100.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.54

Publications

0 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 links:

TARID (HGNC:50506): (TCF21 antisense RNA inducing promoter demethylation)

TARID links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004100.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EYA4	NM_004100.5	MANE Select	c.1294G>T	p.Val432Phe	missense	Exon 15 of 20	NP_004091.3
EYA4	NM_001301013.2		c.1312G>T	p.Val438Phe	missense	Exon 15 of 20	NP_001287942.1	F2Z2Y1
EYA4	NM_172105.4		c.1294G>T	p.Val432Phe	missense	Exon 15 of 20	NP_742103.1	O95677-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EYA4	ENST00000355286.12	TSL:1 MANE Select	c.1294G>T	p.Val432Phe	missense	Exon 15 of 20	ENSP00000347434.7	O95677-1
TARID	ENST00000607033.5	TSL:1	n.2262-5412C>A		intron	N/A
EYA4	ENST00000531901.5	TSL:2	c.1312G>T	p.Val438Phe	missense	Exon 15 of 20	ENSP00000432770.1	F2Z2Y1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dilated cardiomyopathy 1J (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

3.1

PhyloP100

6.5

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.84

MutPred

0.46

Loss of sheet (P = 0.0126)

MVP

0.95

MPC

0.71

ClinPred

1.0

GERP RS

5.4

Varity_R

0.81

gMVP

0.94

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over