rs752953889
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001142800.2(EYS):c.6714delT(p.Ile2239SerfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000522 in 1,551,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001142800.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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EYS | NM_001142800.2 | c.6714delT | p.Ile2239SerfsTer17 | frameshift_variant | Exon 33 of 43 | ENST00000503581.6 | NP_001136272.1 | |
EYS | NM_001292009.2 | c.6714delT | p.Ile2239SerfsTer17 | frameshift_variant | Exon 33 of 44 | NP_001278938.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.6714delT | p.Ile2239SerfsTer17 | frameshift_variant | Exon 33 of 43 | 5 | NM_001142800.2 | ENSP00000424243.1 | ||
EYS | ENST00000370621.7 | c.6714delT | p.Ile2239SerfsTer17 | frameshift_variant | Exon 33 of 44 | 1 | ENSP00000359655.3 | |||
EYS | ENST00000398580.3 | c.27delT | p.Ile10fs | frameshift_variant | Exon 1 of 10 | 5 | ENSP00000381585.3 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000381 AC: 6AN: 157482Hom.: 0 AF XY: 0.0000241 AC XY: 2AN XY: 82906
GnomAD4 exome AF: 0.0000543 AC: 76AN: 1398802Hom.: 0 Cov.: 30 AF XY: 0.0000580 AC XY: 40AN XY: 689780
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74456
ClinVar
Submissions by phenotype
Retinitis pigmentosa 25 Pathogenic:9
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The EYS c.6714del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3_strong. Based on this evidence we have classified this variant as Pathogenic. -
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not provided Pathogenic:4
EYS: PVS1, PM2, PS4:Moderate -
This sequence change creates a premature translational stop signal (p.Ile2239Serfs*17) in the EYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (rs752953889, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 18976725, 21069908, 26667666, 29550188). This variant is also known as p.Pro2238ProfsX16. ClinVar contains an entry for this variant (Variation ID: 357699). For these reasons, this variant has been classified as Pathogenic. -
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Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32218477, 34426522, 31589614, 32037395, 31816670, 34906470, 37643323, 29550188, 25268133, 31964843, 36284460, 37322672, 36819107, 26667666, 25999674, 34662339, 25494902, 21069908, 33576794, 31074760, 34315337, 32531858, 32036094, 18976725) -
Retinitis pigmentosa Pathogenic:4
The EYS c.6714delT (p.Ile2239SerfsTer17) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ile2239SerfsTer17 variant has been reported in a total of four individuals with autosomal recessive retinitis pigmentosa, including two homozygotes and two compound heterozygotes (Collin et al. 2008; Barragan et al. 2010; Katagiri et al. 2014; Ge et al. 2015). The variant was absent from the 1051 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The Ile2239 residue is highly conserved. Based on the evidence from the literature and due to the potential impact of frameshift variants, the p.Ile2239SerfsTer17 variant is classified as likely pathogenic for the autosomal recessive form of retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Variant summary: EYS c.6714delT (p.Ile2239SerfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. At least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.8e-05 in 157482 control chromosomes (gnomAD). c.6714delT has been reported in the literature as a biallelic genotype in multiple individuals affected with Retinitis Pigmentosa and has been shown to segregate with the disease phenotype in at least one family (e.g. Collin_2008, Barragan_2010, Weisschuh_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as either pathogenic (n= 13) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
The p.Ile2239SerfsTer17 variant in EYS was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP5. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -
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Retinal dystrophy Pathogenic:3
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Autosomal recessive retinitis pigmentosa Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at