6-133468648-C-T

Variant names:

• chr6-133468648-C-T
• rs755455584
• NM_004100.5:c.887C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004100.5(EYA4):​c.887C>T​(p.Ser296Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,460,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S296S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.63
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1J

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	NM_004100.5	MANE Select	c.887C>T	p.Ser296Leu	missense	Exon 11 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.887C>T	p.Ser296Leu	missense	Exon 11 of 20	NP_001287942.1
	EYA4	NM_172105.4		c.887C>T	p.Ser296Leu	missense	Exon 11 of 20	NP_742103.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	ENST00000355286.12	TSL:1 MANE Select	c.887C>T	p.Ser296Leu	missense	Exon 11 of 20	ENSP00000347434.7
	EYA4	ENST00000531901.5	TSL:2	c.887C>T	p.Ser296Leu	missense	Exon 11 of 20	ENSP00000432770.1
	EYA4	ENST00000431403.3	TSL:5	c.818C>T	p.Ser273Leu	missense	Exon 10 of 19	ENSP00000404558.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250622 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460664 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726698

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39682

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111106

Other (OTH) AF: 0.0000332 AC: 2 AN: 60328

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1J Uncertain:1

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 296 of the EYA4 protein (p.Ser296Leu). This variant is present in population databases (rs755455584, gnomAD 0.01%). This missense change has been observed in individual(s) with hearing loss (PMID: 32107406). ClinVar contains an entry for this variant (Variation ID: 191661). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EYA4 protein function with a negative predictive value of 80%. 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.

not provided Uncertain:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.018	D
Polyphen		0.97	D
Vest4		0.82
MutPred		0.40		Loss of glycosylation at S296 (P = 0.0068)
MVP		0.88
MPC		0.19
ClinPred		0.60	D
GERP RS		4.9
Varity_R		0.28
gMVP		0.54
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs755455584; hg19: chr6-133789786; COSMIC: COSV62046101; COSMIC: COSV62046101;