chr6-133468590-G-C

Variant names:

• chr6-133468590-G-C
• rs9493627
• NM_004100.5:c.829G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PP3_Moderate BS2

The NM_004100.5(EYA4):​c.829G>C​(p.Gly277Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,836 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G277S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA4	NM_004100.5	c.829G>C	p.Gly277Arg	missense_variant	Exon 11 of 20	ENST00000355286.12	NP_004091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12	c.829G>C	p.Gly277Arg	missense_variant	Exon 11 of 20	1	NM_004100.5	ENSP00000347434.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459836 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726338

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 08, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly277Arg variant in EYA4 has not been previously reported in individuals with hearing loss or in large population studies. A different missense variant at the same position (c.829G>A, Gly277Ser) has been previously reported by our l aboratory as benign; however, this information is not sufficient to rule out a p athogenic role for the p.Gly277Arg variant. Computational prediction tools and c onservation analyses do not provide strong support for or against an impact to t he protein. In summary, the clinical significance of the p.Gly277Arg variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	.;T;D;.;D;.;T;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.0	.;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.5	D;D;D;D;.;.;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D;D;D;D;.;.;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;.;.;D;D
Polyphen		1.0, 1.0, 1.0	.;D;D;D;D;D;D;.
Vest4		0.94
MutPred		0.27		.;.;Gain of phosphorylation at T274 (P = 0.1077);Gain of phosphorylation at T274 (P = 0.1077);Gain of phosphorylation at T274 (P = 0.1077);.;Gain of phosphorylation at T274 (P = 0.1077);.;
MVP		0.94
MPC		0.69
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.66
gMVP		0.75

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: rs9493627; hg19: chr6-133789728;