6-133280707-A-C

Variant names:

• chr6-133280707-A-C
• rs6940715
• NM_004100.5:c.33+5894A>C

Variant summary

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

The NM_001301013.2(EYA4):​c.33+5894A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 152,192 control chromosomes in the GnomAD database, including 1,018 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 0.11 (1018 hom., cov: 32)
• Consequence: EYA4 NM_001301013.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.240
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301013.2. 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.33+5894A>C		intron	N/A	NP_004091.3
	EYA4	NM_001301013.2		c.33+5894A>C		intron	N/A	NP_001287942.1
	EYA4	NM_172105.4		c.33+5894A>C		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.33+5894A>C		intron	N/A	ENSP00000347434.7
	EYA4	ENST00000531901.5	TSL:2	c.33+5894A>C		intron	N/A	ENSP00000432770.1
	EYA4	ENST00000883055.1		c.33+5894A>C		intron	N/A	ENSP00000553114.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16610 AN: 152074 Hom.: 1017 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0680

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0877

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

GnomAD4 genome AF: 0.109 AC: 16631 AN: 152192 Hom.: 1018 Cov.: 32 AF XY: 0.109 AC XY: 8082 AN XY: 74410

African (AFR) AF: 0.141 AC: 5834 AN: 41510

American (AMR) AF: 0.0679 AC: 1038 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 391 AN: 3470

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5188

South Asian (SAS) AF: 0.111 AC: 533 AN: 4820

European-Finnish (FIN) AF: 0.129 AC: 1365 AN: 10606

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7177 AN: 67994

Other (OTH) AF: 0.0863 AC: 182 AN: 2108

Alfa AF: 0.0583 Hom.: 71

Bravo AF: 0.105

Asia WGS AF: 0.0460 AC: 163 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.0
DANN	Benign	0.70
PhyloP100		0.24
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: rs6940715; hg19: chr6-133601845;