chr6-133280124-G-A

Variant names:

• chr6-133280124-G-A
• rs9321395
• NM_004100.5:c.33+5311G>A

Variant summary

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

The NM_004100.5(EYA4):​c.33+5311G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 151,946 control chromosomes in the GnomAD database, including 6,349 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 0.27 (6349 hom., cov: 32)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.318
• Publications: 3 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=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 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.33+5311G>A		intron	N/A	NP_004091.3
	EYA4	NM_001301013.2		c.33+5311G>A		intron	N/A	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.33+5311G>A		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.33+5311G>A		intron	N/A	ENSP00000347434.7	O95677-1
	EYA4	ENST00000531901.5	TSL:2	c.33+5311G>A		intron	N/A	ENSP00000432770.1	F2Z2Y1
	EYA4	ENST00000883055.1		c.33+5311G>A		intron	N/A	ENSP00000553114.1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41528 AN: 151828 Hom.: 6345 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.294

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

GnomAD4 genome AF: 0.274 AC: 41575 AN: 151946 Hom.: 6349 Cov.: 32 AF XY: 0.279 AC XY: 20750 AN XY: 74302

African (AFR) AF: 0.356 AC: 14726 AN: 41422

American (AMR) AF: 0.370 AC: 5657 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 762 AN: 3466

East Asian (EAS) AF: 0.486 AC: 2509 AN: 5158

South Asian (SAS) AF: 0.343 AC: 1653 AN: 4818

European-Finnish (FIN) AF: 0.251 AC: 2643 AN: 10546

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12699 AN: 67954

Other (OTH) AF: 0.297 AC: 625 AN: 2102

Alfa AF: 0.239 Hom.: 1889

Bravo AF: 0.289

Asia WGS AF: 0.435 AC: 1508 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.9
DANN	Benign	0.84
PhyloP100		0.32
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: rs9321395; hg19: chr6-133601262;