rs519332

Variant names:

• chr6-133250134-A-G
• rs519332
• NM_004100.5:c.-66+8385A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-133250134-A-G
• chr6-133250134-A-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.-66+8385A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 152,094 control chromosomes in the GnomAD database, including 48,820 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 0.80 (48820 hom., cov: 31)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.467
• 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: 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

LOC124901231 (HGNC:):

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 = 0.889 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.-66+8385A>G		intron	N/A	NP_004091.3
	EYA4	NM_001301013.2		c.-66+8385A>G		intron	N/A	NP_001287942.1
	EYA4	NM_172105.4		c.-66+8385A>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.-66+8385A>G		intron	N/A	ENSP00000347434.7
	EYA4	ENST00000531901.5	TSL:2	c.-66+8385A>G		intron	N/A	ENSP00000432770.1
	EYA4	ENST00000431403.3	TSL:5	c.-66+8385A>G		intron	N/A	ENSP00000404558.3

Frequencies

GnomAD3 genomes AF: 0.797 AC: 121124 AN: 151976 Hom.: 48776 Cov.: 31

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.692

Gnomad AMR AF: 0.825

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.860

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.754

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.737

Gnomad OTH AF: 0.772

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

GnomAD4 genome AF: 0.797 AC: 121223 AN: 152094 Hom.: 48820 Cov.: 31 AF XY: 0.798 AC XY: 59284 AN XY: 74322

African (AFR) AF: 0.896 AC: 37210 AN: 41514

American (AMR) AF: 0.825 AC: 12613 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2430 AN: 3472

East Asian (EAS) AF: 0.860 AC: 4418 AN: 5138

South Asian (SAS) AF: 0.836 AC: 4025 AN: 4812

European-Finnish (FIN) AF: 0.754 AC: 7970 AN: 10566

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.737 AC: 50087 AN: 67982

Other (OTH) AF: 0.772 AC: 1632 AN: 2114

Alfa AF: 0.756 Hom.: 11330

Bravo AF: 0.805

Asia WGS AF: 0.856 AC: 2974 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	0.12
DANN	Benign	0.38
PhyloP100		-0.47
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: rs519332; hg19: chr6-133571272;