rs1554261713

Variant names:

• chr6-133461129-G-T
• rs1554261713
• NM_004100.5:c.386G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001301013.2(EYA4):​c.386G>T​(p.Gly129Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G129S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EYA4 NM_001301013.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36
• 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]

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.386G>T	p.Gly129Val	missense	Exon 7 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.386G>T	p.Gly129Val	missense	Exon 7 of 20	NP_001287942.1
	EYA4	NM_172105.4		c.386G>T	p.Gly129Val	missense	Exon 7 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.386G>T	p.Gly129Val	missense	Exon 7 of 20	ENSP00000347434.7
	EYA4	ENST00000531901.5	TSL:2	c.386G>T	p.Gly129Val	missense	Exon 7 of 20	ENSP00000432770.1
	EYA4	ENST00000883055.1		c.386G>T	p.Gly129Val	missense	Exon 8 of 21	ENSP00000553114.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.084	T
Polyphen		0.99	D
Vest4		0.90
MutPred		0.22		Loss of glycosylation at S128 (P = 0.0646)
MVP		0.92
MPC		0.71
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.55
gMVP		0.68
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1554261713; hg19: chr6-133782267;