rs1060502993

Variant names:

• chr6-133462747-A-G
• rs1060502993
• NM_004100.5:c.707A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-133462747-A-G
• chr6-133462747-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001301013.2(EYA4):​c.707A>G​(p.Tyr236Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y236H) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: EYA4 NM_001301013.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.94
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301013.2. 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.707A>G	p.Tyr236Cys	missense	Exon 9 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.707A>G	p.Tyr236Cys	missense	Exon 9 of 20	NP_001287942.1
	EYA4	NM_172105.4		c.707A>G	p.Tyr236Cys	missense	Exon 9 of 20	NP_742103.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	ENST00000355286.12	TSL:1 MANE Select	c.707A>G	p.Tyr236Cys	missense	Exon 9 of 20	ENSP00000347434.7
	EYA4	ENST00000531901.5	TSL:2	c.707A>G	p.Tyr236Cys	missense	Exon 9 of 20	ENSP00000432770.1
	EYA4	ENST00000883055.1		c.707A>G	p.Tyr236Cys	missense	Exon 10 of 21	ENSP00000553114.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74310

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1J (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.28		Gain of catalytic residue at P235 (P = 0.0157)
MVP		0.96
MPC		0.70
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.72
gMVP		0.70
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1060502993; hg19: chr6-133783885;