rs17854076

Variant names:

• chr6-133464837-G-A
• rs17854076
• NM_004100.5:c.783G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004100.5(EYA4):​c.783G>A​(p.Thr261Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,610,040 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T261T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: EYA4 NM_004100.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -1.47
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 6-133464837-G-A is Benign according to our data. Variant chr6-133464837-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44772.
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00129 (197/152156) while in subpopulation NFE AF = 0.00253 (172/68002). AF 95% confidence interval is 0.00222. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 197 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	NM_004100.5	MANE Select	c.783G>A	p.Thr261Thr	synonymous	Exon 10 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.783G>A	p.Thr261Thr	synonymous	Exon 10 of 20	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.783G>A	p.Thr261Thr	synonymous	Exon 10 of 20	NP_742103.1	O95677-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	ENST00000355286.12	TSL:1 MANE Select	c.783G>A	p.Thr261Thr	synonymous	Exon 10 of 20	ENSP00000347434.7	O95677-1
	EYA4	ENST00000531901.5	TSL:2	c.783G>A	p.Thr261Thr	synonymous	Exon 10 of 20	ENSP00000432770.1	F2Z2Y1
	EYA4	ENST00000883055.1		c.783G>A	p.Thr261Thr	synonymous	Exon 11 of 21	ENSP00000553114.1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 197 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00120 AC: 301 AN: 250268 AF XY: 0.00117

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00222

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.00151 AC: 2208 AN: 1457884 Hom.: 6 Cov.: 28 AF XY: 0.00161 AC XY: 1170 AN XY: 725504

African (AFR) AF: 0.000210 AC: 7 AN: 33368

American (AMR) AF: 0.000426 AC: 19 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86166

European-Finnish (FIN) AF: 0.00119 AC: 63 AN: 53018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00183 AC: 2031 AN: 1109136

Other (OTH) AF: 0.00123 AC: 74 AN: 60188

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74372

African (AFR) AF: 0.000169 AC: 7 AN: 41526

American (AMR) AF: 0.000262 AC: 4 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000661 AC: 7 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00253 AC: 172 AN: 68002

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00165 Hom.: 0

Bravo AF: 0.00118

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00208

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	1	Dilated cardiomyopathy 1J (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 10 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.0
DANN	Benign	0.49
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17854076; hg19: chr6-133785975; COSMIC: COSV62055787; COSMIC: COSV62055787;