chr6-133259273-G-T

Variant names:

• chr6-133259273-G-T
• rs572004
• NM_004100.5:c.-65-15443G>T

Variant summary

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

The NM_004100.5(EYA4):​c.-65-15443G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 152,156 control chromosomes in the GnomAD database, including 46,468 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 0.78 (46468 hom., cov: 32)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.308
• Publications: 5 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.88 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	NM_004100.5	MANE Select	c.-65-15443G>T		intron	N/A	NP_004091.3
	EYA4	NM_001301013.2		c.-65-15443G>T		intron	N/A	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.-65-15443G>T		intron	N/A	NP_742103.1	O95677-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	ENST00000355286.12	TSL:1 MANE Select	c.-65-15443G>T		intron	N/A	ENSP00000347434.7	O95677-1
	EYA4	ENST00000531901.5	TSL:2	c.-65-15443G>T		intron	N/A	ENSP00000432770.1	F2Z2Y1
	EYA4	ENST00000883055.1		c.-65-15443G>T		intron	N/A	ENSP00000553114.1

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118098 AN: 152040 Hom.: 46423 Cov.: 32

Gnomad AFR AF: 0.888

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.806

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.753

Gnomad FIN AF: 0.728

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.747

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

GnomAD4 genome AF: 0.777 AC: 118199 AN: 152156 Hom.: 46468 Cov.: 32 AF XY: 0.776 AC XY: 57712 AN XY: 74396

African (AFR) AF: 0.888 AC: 36899 AN: 41560

American (AMR) AF: 0.806 AC: 12320 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2264 AN: 3468

East Asian (EAS) AF: 0.855 AC: 4431 AN: 5180

South Asian (SAS) AF: 0.752 AC: 3625 AN: 4820

European-Finnish (FIN) AF: 0.728 AC: 7691 AN: 10570

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.715 AC: 48585 AN: 67954

Other (OTH) AF: 0.746 AC: 1576 AN: 2112

Alfa AF: 0.754 Hom.: 10021

Bravo AF: 0.789

Asia WGS AF: 0.822 AC: 2856 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.42
DANN	Benign	0.51
PhyloP100		-0.31
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: rs572004; hg19: chr6-133580411; COSMIC: COSV62059394;