rs761238771
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001142800.2(EYS):c.4350_4356del(p.Ile1451ProfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,551,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L1450L) has been classified as Likely benign. 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYS | NM_001142800.2 | c.4350_4356del | p.Ile1451ProfsTer3 | frameshift_variant | 26/43 | ENST00000503581.6 | |
EYS | NM_001292009.2 | c.4350_4356del | p.Ile1451ProfsTer3 | frameshift_variant | 26/44 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.4350_4356del | p.Ile1451ProfsTer3 | frameshift_variant | 26/43 | 5 | NM_001142800.2 | A2 | |
EYS | ENST00000370621.7 | c.4350_4356del | p.Ile1451ProfsTer3 | frameshift_variant | 26/44 | 1 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000987 AC: 15AN: 152020Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000783 AC: 12AN: 153194Hom.: 0 AF XY: 0.0000615 AC XY: 5AN XY: 81256
GnomAD4 exome AF: 0.0000943 AC: 132AN: 1399160Hom.: 0 AF XY: 0.0000754 AC XY: 52AN XY: 690088
GnomAD4 genome ? AF: 0.0000987 AC: 15AN: 152020Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7AN XY: 74238
ClinVar
Submissions by phenotype
not provided Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 07, 2022 | 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: 25491159, 32531858, 21217109, 31074760, 30718709, 32037395, 20537394) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change creates a premature translational stop signal (p.Ile1451Profs*3) 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 (rs761238771, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive retinitis pigmentosa (PMID: 20537394, 24265693, 31074760). ClinVar contains an entry for this variant (Variation ID: 195936). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 24, 2014 | - - |
Retinitis pigmentosa 25 Pathogenic:6
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The EYS c.4350_4356del 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, PP1. Based on this evidence we have classified this variant as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Sep 16, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 21, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Mar 24, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 12, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 24, 2021 | - - |
Retinitis pigmentosa Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Sep 23, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | The p.Ile1451ProfsTer3 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. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 26, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at