rs75133151

Variant names:

• chr6-133468666-G-A
• rs75133151
• NM_004100.5:c.905G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004100.5(EYA4):​c.905G>A​(p.Gly302Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00153 in 1,612,918 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (22 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 5.17
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007827669).
• BP6: Variant 6-133468666-G-A is Benign according to our data. Variant chr6-133468666-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00789 (1200/152180) while in subpopulation AFR AF = 0.0268 (1114/41556). AF 95% confidence interval is 0.0255. There are 10 homozygotes in GnomAd4. There are 563 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1200 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.905G>A	p.Gly302Asp	missense	Exon 11 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.905G>A	p.Gly302Asp	missense	Exon 11 of 20	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.905G>A	p.Gly302Asp	missense	Exon 11 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.905G>A	p.Gly302Asp	missense	Exon 11 of 20	ENSP00000347434.7	O95677-1
	EYA4	ENST00000531901.5	TSL:2	c.905G>A	p.Gly302Asp	missense	Exon 11 of 20	ENSP00000432770.1	F2Z2Y1
	EYA4	ENST00000883055.1		c.905G>A	p.Gly302Asp	missense	Exon 12 of 21	ENSP00000553114.1

Frequencies

GnomAD3 genomes AF: 0.00790 AC: 1201 AN: 152060 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00414

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00212 AC: 531 AN: 250630 AF XY: 0.00152

Gnomad AFR exome AF: 0.0277

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.000869 AC: 1270 AN: 1460738 Hom.: 22 Cov.: 32 AF XY: 0.000771 AC XY: 560 AN XY: 726710

African (AFR) AF: 0.0283 AC: 946 AN: 33412

American (AMR) AF: 0.00155 AC: 69 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5762

European-Non Finnish (NFE) AF: 0.000129 AC: 143 AN: 1111180

Other (OTH) AF: 0.00161 AC: 97 AN: 60328

GnomAD4 genome AF: 0.00789 AC: 1200 AN: 152180 Hom.: 10 Cov.: 32 AF XY: 0.00757 AC XY: 563 AN XY: 74390

African (AFR) AF: 0.0268 AC: 1114 AN: 41556

American (AMR) AF: 0.00413 AC: 63 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67990

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00214 Hom.: 14

Bravo AF: 0.00903

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00259 AC: 314

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Dilated cardiomyopathy 1J (2)
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 10 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0078	T
MetaSVM	Uncertain	0.046	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.046	D
Polyphen		0.38	B
Vest4		0.71
MVP		0.79
MPC		0.49
ClinPred		0.020	T
GERP RS		5.6
Varity_R		0.22
gMVP		0.51
Mutation Taster		=99/1	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: rs75133151; hg19: chr6-133789804;