6-133483033-G-T

Variant names:

• chr6-133483033-G-T
• rs143936434
• NM_004100.5:c.1109G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_004100.5(EYA4):​c.1109G>T​(p.Arg370Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R370H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EYA4 NM_004100.5 missense, splice_region
• Scores: Splicing: ADA: 0.9826
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• 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: 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-133483033-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163451.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.1109G>T	p.Arg370Leu	missense splice_region	Exon 13 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.1127G>T	p.Arg376Leu	missense splice_region	Exon 13 of 20	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.1109G>T	p.Arg370Leu	missense splice_region	Exon 13 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.1109G>T	p.Arg370Leu	missense splice_region	Exon 13 of 20	ENSP00000347434.7	O95677-1
	EYA4	ENST00000531901.5	TSL:2	c.1127G>T	p.Arg376Leu	missense splice_region	Exon 13 of 20	ENSP00000432770.1	F2Z2Y1
	EYA4	ENST00000883055.1		c.1127G>T	p.Arg376Leu	missense splice_region	Exon 14 of 21	ENSP00000553114.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459656 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726250

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110396

Other (OTH) AF: 0.00 AC: 0 AN: 60270

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		10
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.49		Loss of disorder (P = 0.0806)
MVP		0.96
MPC		0.66
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.80
gMVP		0.81
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.88
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: rs143936434; hg19: chr6-133804171;