Variant 6-133506110-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004100.5(EYA4):c.1196C>T(p.Pro399Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,562 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P399S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EYA4
NM_004100.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.58

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA4	NM_004100.5 linkuse as main transcript	c.1196C>T	p.Pro399Leu	missense_variant	14/20	ENST00000355286.12
TARID	NR_109982.1 linkuse as main transcript	n.2524G>A		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA4	ENST00000355286.12 linkuse as main transcript	c.1196C>T	p.Pro399Leu	missense_variant	14/20	1	NM_004100.5	P4	O95677-1
TARID	ENST00000607033.5 linkuse as main transcript	n.2500G>A		non_coding_transcript_exon_variant	8/9	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442562

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2021

The p.P399L variant (also known as c.1196C>T), located in coding exon 13 of the EYA4 gene, results from a C to T substitution at nucleotide position 1196. The proline at codon 399 is replaced by leucine, 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

0.33

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

.;T;D;.;D;.;D;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;.;D;D;D;D;D

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.74

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

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.7

.;.;L;L;L;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.7

D;D;D;D;.;.;D;D

REVEL

Uncertain

0.55

Sift

Benign

0.065

T;T;T;T;.;.;D;D

Sift4G

Benign

0.34

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

Polyphen

0.0070, 0.0010, 0.28

.;B;B;B;B;B;B;.

Vest4

0.73

MutPred

0.47

.;.;.;.;.;.;Loss of catalytic residue at P405 (P = 0.0072);.;

MVP

0.86

MPC

0.21

ClinPred

0.99

GERP RS

5.2

Varity_R

0.29

gMVP

0.77

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over