chr6-133446698-C-G

Position:

• chr6-133446698-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_004100.5(EYA4):​c.152C>G​(p.Ser51Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. S51F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-133446698-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.40023267).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA4	NM_004100.5	c.152C>G	p.Ser51Cys	missense_variant	4/20	ENST00000355286.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA4	ENST00000355286.12	c.152C>G	p.Ser51Cys	missense_variant	4/20	1	NM_004100.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251418 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135880

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461658 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	.;T;T;.;T;.;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.81	L;.;L;L;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.83	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.029	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.023	D;D;T;T;D;T;T;D
Polyphen		1.0, 1.0, 0.99, 1.0	.;D;D;D;D;D;D;.
Vest4		0.54
MutPred		0.25		Loss of phosphorylation at S51 (P = 0.0233);Loss of phosphorylation at S51 (P = 0.0233);Loss of phosphorylation at S51 (P = 0.0233);Loss of phosphorylation at S51 (P = 0.0233);Loss of phosphorylation at S51 (P = 0.0233);Loss of phosphorylation at S51 (P = 0.0233);Loss of phosphorylation at S51 (P = 0.0233);Loss of phosphorylation at S51 (P = 0.0233);
MVP		0.91
MPC		0.53
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.15
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs542906126; hg19: chr6-133767836;