6-63720752-A-ACC
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001142800.2(EYS):c.9277_9278dupGG(p.Arg3094ValfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 1,398,352 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001142800.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EYS | NM_001142800.2 | c.9277_9278dupGG | p.Arg3094ValfsTer4 | frameshift_variant | Exon 43 of 43 | ENST00000503581.6 | NP_001136272.1 | |
PHF3 | NM_001370348.2 | c.*7045_*7046dupCC | 3_prime_UTR_variant | Exon 16 of 16 | ENST00000262043.8 | NP_001357277.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.9277_9278dupGG | p.Arg3094ValfsTer4 | frameshift_variant | Exon 43 of 43 | 5 | NM_001142800.2 | ENSP00000424243.1 | ||
EYS | ENST00000370621.7 | c.9340_9341dupGG | p.Arg3115ValfsTer4 | frameshift_variant | Exon 44 of 44 | 1 | ENSP00000359655.3 | |||
PHF3 | ENST00000262043.8 | c.*7045_*7046dupCC | 3_prime_UTR_variant | Exon 16 of 16 | 5 | NM_001370348.2 | ENSP00000262043.4 | |||
PHF3 | ENST00000505138.1 | c.361+9391_361+9392dupCC | intron_variant | Intron 3 of 4 | 3 | ENSP00000421417.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000644 AC: 9AN: 1398352Hom.: 0 Cov.: 32 AF XY: 0.00000870 AC XY: 6AN XY: 689678
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the EYS protein. Other variant(s) that disrupt this region (p.Tyr3135*) have been determined to be pathogenic (PMID: 18976725, 31074760, 29159838, 30337596). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with retinitis pigmentosa (PMID: 22581970). ClinVar contains an entry for this variant (Variation ID: 224759). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the EYS gene (p.Arg3094Valfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the EYS protein. -
Retinitis pigmentosa 25 Pathogenic:1
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Retinal dystrophy Pathogenic:1
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Retinitis pigmentosa Pathogenic:1
Variant summary: EYS c.9277_9278dupGG (p.Arg3094ValfsX4) is located in exon 43 (i.e. in the last exon), and results in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, that removes a part of the fifth laminin G domain (amino acids 2975-3165; IPR001791). Truncations downstream of this position have been reported in affected individuals (HGMD). The variant was absent in 155724 control chromosomes (gnomAD). c.9277_9278dupGG has been reported in the literature in at least one compound heterozygous individual affected with inherited retinal disease (O'Sullivan_2012, Ellingford_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at