6-133274787-G-A

Position:

• chr6-133274787-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000355286.12(EYA4):​c.7G>A​(p.Asp3Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D3D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EYA4 ENST00000355286.12 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23308325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA4	NM_004100.5	c.7G>A	p.Asp3Asn	missense_variant	2/20	ENST00000355286.12	NP_004091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12	c.7G>A	p.Asp3Asn	missense_variant	2/20	1	NM_004100.5	ENSP00000347434	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1J Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 05, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 2492559). This variant has not been reported in the literature in individuals affected with EYA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 3 of the EYA4 protein (p.Asp3Asn). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.7G>A (p.D3N) alteration is located in exon 2 (coding exon 1) of the EYA4 gene. This alteration results from a G to A substitution at nucleotide position 7, causing the aspartic acid (D) at amino acid position 3 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0056	.;T;T;.;T;.;T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;.;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	-0.34	N;.;N;N;N;N;.;.
MutationTaster	Benign	0.77	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.32	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.094	T;T;D;D;D;D;D;D
Sift4G	Benign	0.44	T;T;T;T;T;T;T;T
Polyphen		0.88, 0.0020	.;P;B;B;B;P;B;.
Vest4		0.44
MutPred		0.12		Loss of phosphorylation at S4 (P = 0.2032);Loss of phosphorylation at S4 (P = 0.2032);Loss of phosphorylation at S4 (P = 0.2032);Loss of phosphorylation at S4 (P = 0.2032);Loss of phosphorylation at S4 (P = 0.2032);Loss of phosphorylation at S4 (P = 0.2032);Loss of phosphorylation at S4 (P = 0.2032);Loss of phosphorylation at S4 (P = 0.2032);
MVP		0.85
MPC		0.14
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.12
gMVP		0.13

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.

Other links and lift over

hg19: chr6-133595925;