rs727503053

Variant names:

• chr6-133525066-CTTATG-C
• rs727503053
• NM_004100.5:c.1739-85_1739-81delATGTT

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_004100.5(EYA4):​c.1739-85_1739-81delATGTT variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,368 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 10.0
• Publications: 2 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]

TARID (HGNC:50506): (TCF21 antisense RNA inducing promoter demethylation)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BS2: High AC in GnomAdExome4 at 33 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.1739-85_1739-81delATGTT		intron	N/A	NP_004091.3
	EYA4	NM_172105.4		c.1793_1797delATGTT	p.Tyr598CysfsTer8	frameshift	Exon 19 of 20	NP_742103.1
	EYA4	NM_001370458.1		c.1724_1728delATGTT	p.Tyr575CysfsTer8	frameshift	Exon 18 of 19	NP_001357387.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	ENST00000355286.12	TSL:1 MANE Select	c.1739-85_1739-81delATGTT		intron	N/A	ENSP00000347434.7
	TARID	ENST00000607033.5	TSL:1	n.2261+10709_2261+10713delCATAA		intron	N/A
	EYA4	ENST00000525849.7	TSL:5	c.1724_1728delATGTT	p.Tyr575CysfsTer8	frameshift	Exon 18 of 19	ENSP00000433219.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251088 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461368 Hom.: 0 AF XY: 0.0000179 AC XY: 13 AN XY: 726984

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111678

Other (OTH) AF: 0.0000166 AC: 1 AN: 60360

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 07, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Tyr598fs va riant in EYA4 has not been reported in individuals affected with hearing loss or in large population studies. This frameshift variant is located in exon 18A (al so referred to as exon 19 in the literature) present in alternate splice isoform s of the EYA4 gene, and is predicted to alter the protein?s amino acid sequence beginning at position 598 leading to a premature termination codon 8 amino acids downstream. While the major transcript of EYA4 (NM_004100.4) does not contain e xon 18A, studies have shown that this exon is expressed in human fetal cochlea ( Wayne 2001). However, without additional studies, it is unclear whether this tru ncated product is related to this individual's hearing loss. In summary, additio nal information is needed to determine the clinical significance of this variant .

not provided Uncertain:1

Mar 18, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; Reported using an alternate transcript of the gene; Frameshift variant predicted to result in abnormal protein length as the last 42 amino acids are replaced with 7 different amino acids with an unclear effect on protein function

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=17/183	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727503053; hg19: chr6-133846204;