rs9493627

Variant names:

• chr6-133468590-G-A
• rs9493627
• NM_004100.5:c.829G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-133468590-G-A
• chr6-133468590-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004100.5(EYA4):​c.829G>A​(p.Gly277Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,609,232 control chromosomes in the GnomAD database, including 91,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G277D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.38 (11687 hom., cov: 31)
  • Exomes 𝑓: 0.33 (79579 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 9.52
• Publications: 62 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=0.0013802946).
• BP6: Variant 6-133468590-G-A is Benign according to our data. Variant chr6-133468590-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.533 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	NM_004100.5	MANE Select	c.829G>A	p.Gly277Ser	missense	Exon 11 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.829G>A	p.Gly277Ser	missense	Exon 11 of 20	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.829G>A	p.Gly277Ser	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.829G>A	p.Gly277Ser	missense	Exon 11 of 20	ENSP00000347434.7	O95677-1
	EYA4	ENST00000531901.5	TSL:2	c.829G>A	p.Gly277Ser	missense	Exon 11 of 20	ENSP00000432770.1	F2Z2Y1
	EYA4	ENST00000883055.1		c.829G>A	p.Gly277Ser	missense	Exon 12 of 21	ENSP00000553114.1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57117 AN: 151550 Hom.: 11671 Cov.: 31

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.333 AC: 83517 AN: 250774 AF XY: 0.334

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.281

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.353

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.326 AC: 475819 AN: 1457562 Hom.: 79579 Cov.: 34 AF XY: 0.328 AC XY: 237952 AN XY: 725380

African (AFR) AF: 0.544 AC: 18153 AN: 33342

American (AMR) AF: 0.288 AC: 12829 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7887 AN: 26070

East Asian (EAS) AF: 0.353 AC: 13989 AN: 39662

South Asian (SAS) AF: 0.388 AC: 33416 AN: 86168

European-Finnish (FIN) AF: 0.248 AC: 13220 AN: 53382

Middle Eastern (MID) AF: 0.395 AC: 2275 AN: 5754

European-Non Finnish (NFE) AF: 0.319 AC: 353902 AN: 1108370

Other (OTH) AF: 0.335 AC: 20148 AN: 60212

GnomAD4 genome AF: 0.377 AC: 57173 AN: 151670 Hom.: 11687 Cov.: 31 AF XY: 0.372 AC XY: 27593 AN XY: 74098

African (AFR) AF: 0.538 AC: 22264 AN: 41350

American (AMR) AF: 0.323 AC: 4900 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1016 AN: 3464

East Asian (EAS) AF: 0.345 AC: 1774 AN: 5146

South Asian (SAS) AF: 0.406 AC: 1950 AN: 4802

European-Finnish (FIN) AF: 0.226 AC: 2384 AN: 10560

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21725 AN: 67850

Other (OTH) AF: 0.367 AC: 772 AN: 2106

Alfa AF: 0.338 Hom.: 44415

Bravo AF: 0.388

TwinsUK AF: 0.306 AC: 1136

ALSPAC AF: 0.328 AC: 1263

ESP6500AA AF: 0.520 AC: 2291

ESP6500EA AF: 0.313 AC: 2690

ExAC AF: 0.341 AC: 41411

Asia WGS AF: 0.357 AC: 1241 AN: 3478

EpiCase AF: 0.325

EpiControl AF: 0.333

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	Dilated cardiomyopathy 1J (3)
-	-	2	Autosomal dominant nonsyndromic hearing loss 10 (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 10;C1854368:Dilated cardiomyopathy 1J (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0014	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.9	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.42
Sift	Benign	0.18	T
Sift4G	Benign	0.25	T
Polyphen		0.97	D
Vest4		0.43
MPC		0.63
ClinPred		0.023	T
GERP RS		5.5
Varity_R		0.27
gMVP		0.67
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs9493627; hg19: chr6-133789728; COSMIC: COSV62047183; COSMIC: COSV62047183;