6-133406111-A-G

Variant names:

• chr6-133406111-A-G
• rs17062478
• NM_004100.5:c.83+23670A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004100.5(EYA4):​c.83+23670A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0768 in 152,194 control chromosomes in the GnomAD database, including 657 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.077 (657 hom., cov: 32)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.456
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

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.83+23670A>G		intron	N/A	NP_004091.3
	EYA4	NM_001301013.2		c.83+23670A>G		intron	N/A	NP_001287942.1
	EYA4	NM_172105.4		c.83+23670A>G		intron	N/A	NP_742103.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	ENST00000355286.12	TSL:1 MANE Select	c.83+23670A>G		intron	N/A	ENSP00000347434.7
	EYA4	ENST00000531901.5	TSL:2	c.83+23670A>G		intron	N/A	ENSP00000432770.1
	EYA4	ENST00000431403.3	TSL:5	c.83+23670A>G		intron	N/A	ENSP00000404558.3

Frequencies

GnomAD3 genomes AF: 0.0767 AC: 11670 AN: 152078 Hom.: 651 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0544

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0842

Gnomad OTH AF: 0.0794

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0768 AC: 11681 AN: 152194 Hom.: 657 Cov.: 32 AF XY: 0.0778 AC XY: 5788 AN XY: 74400

African (AFR) AF: 0.0240 AC: 998 AN: 41532

American (AMR) AF: 0.129 AC: 1976 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0544 AC: 189 AN: 3472

East Asian (EAS) AF: 0.223 AC: 1152 AN: 5162

South Asian (SAS) AF: 0.170 AC: 820 AN: 4826

European-Finnish (FIN) AF: 0.0527 AC: 558 AN: 10586

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0842 AC: 5725 AN: 68012

Other (OTH) AF: 0.0806 AC: 170 AN: 2110

Alfa AF: 0.0895 Hom.: 291

Bravo AF: 0.0797

Asia WGS AF: 0.180 AC: 623 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.0
DANN	Benign	0.70
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs17062478; hg19: chr6-133727249;