rs211433

Variant names:

• chr6-133289612-A-G
• rs211433
• NM_004100.5:c.33+14799A>G

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+14799A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 152,110 control chromosomes in the GnomAD database, including 9,639 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 0.35 (9639 hom., cov: 32)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.110
• Publications: 1 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA4	NM_004100.5	c.33+14799A>G		intron_variant	Intron 2 of 19	ENST00000355286.12	NP_004091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12	c.33+14799A>G		intron_variant	Intron 2 of 19	1	NM_004100.5	ENSP00000347434.7

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53212 AN: 151992 Hom.: 9630 Cov.: 32

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.330

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.321

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

GnomAD4 genome AF: 0.350 AC: 53252 AN: 152110 Hom.: 9639 Cov.: 32 AF XY: 0.344 AC XY: 25560 AN XY: 74354

African (AFR) AF: 0.430 AC: 17814 AN: 41470

American (AMR) AF: 0.294 AC: 4495 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 992 AN: 3468

East Asian (EAS) AF: 0.189 AC: 976 AN: 5172

South Asian (SAS) AF: 0.288 AC: 1391 AN: 4832

European-Finnish (FIN) AF: 0.332 AC: 3513 AN: 10574

Middle Eastern (MID) AF: 0.324 AC: 94 AN: 290

European-Non Finnish (NFE) AF: 0.340 AC: 23116 AN: 67986

Other (OTH) AF: 0.319 AC: 675 AN: 2116

Alfa AF: 0.342 Hom.: 4847

Bravo AF: 0.350

Asia WGS AF: 0.239 AC: 834 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.1
DANN	Benign	0.38
PhyloP100		0.11
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: rs211433; hg19: chr6-133610750;