chr6-64626235-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001142800.2(EYS):c.3454G>A(p.Gly1152Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,527,592 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 (★★).
Frequency
Consequence
NM_001142800.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.3454G>A | p.Gly1152Arg | missense_variant | Exon 23 of 43 | 5 | NM_001142800.2 | ENSP00000424243.1 | ||
EYS | ENST00000370621.7 | c.3454G>A | p.Gly1152Arg | missense_variant | Exon 23 of 44 | 1 | ENSP00000359655.3 | |||
EYS | ENST00000330816.5 | n.75G>A | non_coding_transcript_exon_variant | Exon 2 of 4 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000527 AC: 8AN: 151934Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000113 AC: 15AN: 133052Hom.: 0 AF XY: 0.0000991 AC XY: 7AN XY: 70622
GnomAD4 exome AF: 0.0000502 AC: 69AN: 1375658Hom.: 0 Cov.: 28 AF XY: 0.0000457 AC XY: 31AN XY: 677646
GnomAD4 genome AF: 0.0000527 AC: 8AN: 151934Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74182
ClinVar
Submissions by phenotype
Retinitis pigmentosa 25 Uncertain:2
- -
- -
not specified Uncertain:1
Variant summary: EYS c.3454G>A (p.Gly1152Arg) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 133052 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00011 vs 0.0034), allowing no conclusion about variant significance. c.3454G>A has been reported in the literature in individuals affected with Retinitis Pigmentosa, without strong evidence for causality (Xu_2014, Katagiri_2014, Iwanami_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24938718, 25268133, 31814702, 36675693). ClinVar contains an entry for this variant (Variation ID: 554359). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Autosomal recessive retinitis pigmentosa Uncertain:1
- -
not provided Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1152 of the EYS protein (p.Gly1152Arg). This variant is present in population databases (rs371491059, gnomAD 0.2%). This missense change has been observed in individuals with autosomal recessive retinitis pigmentosa (PMID: 24938718). ClinVar contains an entry for this variant (Variation ID: 554359). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EYS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Retinal dystrophy Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at