rs200300314

Variant names:

• chr6-133515422-A-G
• rs200300314
• NM_004100.5:c.1603A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004100.5(EYA4):​c.1603A>G​(p.Ile535Val) variant causes a missense change. The variant allele was found at a frequency of 0.000047 in 1,575,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.94
• Publications: 0 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]

TARID (HGNC:50506): (TCF21 antisense RNA inducing promoter demethylation)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 5 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.1603A>G	p.Ile535Val	missense	Exon 17 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.1621A>G	p.Ile541Val	missense	Exon 17 of 20	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.1603A>G	p.Ile535Val	missense	Exon 17 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.1603A>G	p.Ile535Val	missense	Exon 17 of 20	ENSP00000347434.7	O95677-1
	TARID	ENST00000607033.5	TSL:1	n.2262-8101T>C		intron	N/A
	EYA4	ENST00000531901.5	TSL:2	c.1621A>G	p.Ile541Val	missense	Exon 17 of 20	ENSP00000432770.1	F2Z2Y1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251452 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000485 AC: 69 AN: 1423488 Hom.: 0 Cov.: 25 AF XY: 0.0000394 AC XY: 28 AN XY: 710640

African (AFR) AF: 0.00 AC: 0 AN: 32716

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000622 AC: 67 AN: 1077154

Other (OTH) AF: 0.0000169 AC: 1 AN: 59032

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated cardiomyopathy 1J (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.39
Sift	Benign	0.030	D
Sift4G	Benign	0.087	T
Polyphen		0.041	B
Vest4		0.33
MutPred		0.50		Gain of ubiquitination at K537 (P = 0.0913)
MVP		0.76
MPC		1.2
ClinPred		0.69	D
GERP RS		5.7
Varity_R		0.17
gMVP		0.55
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200300314; hg19: chr6-133836560;