rs17301249

Variant names:

• chr6-133291776-G-C
• rs17301249
• NM_004100.5:c.33+16963G>C

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+16963G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 152,086 control chromosomes in the GnomAD database, including 1,754 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 0.15 (1754 hom., cov: 32)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0310
• Publications: 17 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 (NFE) allele frequency at 95% confidence interval = 0.166 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.33+16963G>C		intron	N/A	NP_004091.3
	EYA4	NM_001301013.2		c.33+16963G>C		intron	N/A	NP_001287942.1
	EYA4	NM_172105.4		c.33+16963G>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+16963G>C		intron	N/A	ENSP00000347434.7
	EYA4	ENST00000531901.5	TSL:2	c.33+16963G>C		intron	N/A	ENSP00000432770.1
	EYA4	ENST00000431403.3	TSL:5	c.33+16963G>C		intron	N/A	ENSP00000404558.3

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22795 AN: 151968 Hom.: 1753 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.127

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

GnomAD4 genome AF: 0.150 AC: 22797 AN: 152086 Hom.: 1754 Cov.: 32 AF XY: 0.148 AC XY: 11035 AN XY: 74322

African (AFR) AF: 0.139 AC: 5747 AN: 41464

American (AMR) AF: 0.127 AC: 1943 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 417 AN: 3472

East Asian (EAS) AF: 0.154 AC: 794 AN: 5168

South Asian (SAS) AF: 0.119 AC: 573 AN: 4818

European-Finnish (FIN) AF: 0.129 AC: 1362 AN: 10570

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11473 AN: 67990

Other (OTH) AF: 0.127 AC: 268 AN: 2112

Alfa AF: 0.159 Hom.: 249

Bravo AF: 0.148

Asia WGS AF: 0.141 AC: 492 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	2.1
DANN	Benign	0.37
PhyloP100		-0.031
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: rs17301249; hg19: chr6-133612914;