rs1554263071

Positions:

• chr6-133468710-C-G
• chr6-133468710-C-T

Variant summary

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

The NM_004100.5(EYA4):​c.949C>G​(p.Pro317Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. P317S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52

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=0.107287616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA4	NM_004100.5	c.949C>G	p.Pro317Ala	missense_variant	11/20	ENST00000355286.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA4	ENST00000355286.12	c.949C>G	p.Pro317Ala	missense_variant	11/20	1	NM_004100.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1J Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 16, 2017

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a EYA4-related disease. This sequence change replaces proline with alanine at codon 317 of the EYA4 protein (p.Pro317Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.94
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;.;D;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.82	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N;N;N;N;.;.;N;N
REVEL	Benign	0.20
Sift	Benign	0.15	T;T;T;T;.;.;T;T
Sift4G	Benign	0.18	T;T;T;T;.;.;T;T
Polyphen		0.0	.;B;B;B;B;B;B;.
Vest4		0.19
MutPred		0.29		.;.;Loss of glycosylation at P317 (P = 0.1207);Loss of glycosylation at P317 (P = 0.1207);Loss of glycosylation at P317 (P = 0.1207);.;Loss of glycosylation at P317 (P = 0.1207);.;
MVP		0.61
MPC		0.14
ClinPred		0.34	T
GERP RS		3.9
Varity_R		0.059
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs1554263071; hg19: chr6-133789848;