6-133462487-ATCT-A

Variant names:

• chr6-133462487-ATCT-A
• rs139659489
• NM_004100.5:c.580+14_580+16delTCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004100.5(EYA4):​c.580+14_580+16delTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,946 control chromosomes in the GnomAD database, including 725 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (240 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (485 hom.)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.18
• 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 -16 ACMG points.

• BP6: Variant 6-133462487-ATCT-A is Benign according to our data. Variant chr6-133462487-ATCT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0982 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.580+14_580+16delTCT		intron	N/A	NP_004091.3
	EYA4	NM_001301013.2		c.580+14_580+16delTCT		intron	N/A	NP_001287942.1
	EYA4	NM_172105.4		c.580+14_580+16delTCT		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.580+14_580+16delTCT		intron	N/A	ENSP00000347434.7
	EYA4	ENST00000497350.3	TSL:3	n.682_684delTCT		non_coding_transcript_exon	Exon 1 of 4
	EYA4	ENST00000531901.5	TSL:2	c.580+14_580+16delTCT		intron	N/A	ENSP00000432770.1

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 5090 AN: 152138 Hom.: 238 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0789

Gnomad SAS AF: 0.0441

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0198 AC: 4961 AN: 251064 AF XY: 0.0195

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.00542

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0912

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000617

Gnomad OTH exome AF: 0.00833

GnomAD4 exome AF: 0.00825 AC: 12054 AN: 1461690 Hom.: 485 AF XY: 0.00916 AC XY: 6663 AN XY: 727144

African (AFR) AF: 0.108 AC: 3620 AN: 33458

American (AMR) AF: 0.00631 AC: 282 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26126

East Asian (EAS) AF: 0.0829 AC: 3289 AN: 39688

South Asian (SAS) AF: 0.0426 AC: 3671 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5766

European-Non Finnish (NFE) AF: 0.000352 AC: 391 AN: 1111908

Other (OTH) AF: 0.0121 AC: 732 AN: 60388

GnomAD4 genome AF: 0.0335 AC: 5096 AN: 152256 Hom.: 240 Cov.: 32 AF XY: 0.0339 AC XY: 2526 AN XY: 74436

African (AFR) AF: 0.101 AC: 4187 AN: 41540

American (AMR) AF: 0.0125 AC: 191 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.0785 AC: 406 AN: 5172

South Asian (SAS) AF: 0.0437 AC: 211 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68030

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0147 Hom.: 18

Bravo AF: 0.0374

Asia WGS AF: 0.0420 AC: 144 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Dilated cardiomyopathy 1J (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Nonsyndromic Hearing Loss, Dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs139659489; hg19: chr6-133783625;