rs212769

Variant names:

• chr6-133452410-C-T
• rs212769
• NM_004100.5:c.278-4146C>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.278-4146C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 151,952 control chromosomes in the GnomAD database, including 14,140 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 0.38 (14140 hom., cov: 32)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.590
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA4	NM_004100.5	c.278-4146C>T		intron_variant	Intron 5 of 19	ENST00000355286.12	NP_004091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12	c.278-4146C>T		intron_variant	Intron 5 of 19	1	NM_004100.5	ENSP00000347434.7

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58017 AN: 151834 Hom.: 14148 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.574

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.383

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

GnomAD4 genome AF: 0.382 AC: 58020 AN: 151952 Hom.: 14140 Cov.: 32 AF XY: 0.381 AC XY: 28289 AN XY: 74294

African (AFR) AF: 0.109 AC: 4537 AN: 41512

American (AMR) AF: 0.313 AC: 4779 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 2003 AN: 3468

East Asian (EAS) AF: 0.146 AC: 758 AN: 5186

South Asian (SAS) AF: 0.341 AC: 1643 AN: 4814

European-Finnish (FIN) AF: 0.574 AC: 6054 AN: 10544

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 36949 AN: 67852

Other (OTH) AF: 0.383 AC: 807 AN: 2108

Alfa AF: 0.457 Hom.: 2249

Bravo AF: 0.348

Asia WGS AF: 0.214 AC: 745 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.50
PhyloP100		-0.59
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: rs212769; hg19: chr6-133773548;