chr6-63726614-TGAAAG-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001142800.2(EYS):c.8133_8137delCTTTC(p.Phe2712CysfsTer33) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000367 in 1,551,048 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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EYS | NM_001142800.2 | c.8133_8137delCTTTC | p.Phe2712CysfsTer33 | frameshift_variant | Exon 42 of 43 | ENST00000503581.6 | NP_001136272.1 | |
EYS | NM_001292009.2 | c.8196_8200delCTTTC | p.Phe2733CysfsTer33 | frameshift_variant | Exon 43 of 44 | NP_001278938.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.8133_8137delCTTTC | p.Phe2712CysfsTer33 | frameshift_variant | Exon 42 of 43 | 5 | NM_001142800.2 | ENSP00000424243.1 | ||
EYS | ENST00000370621.7 | c.8196_8200delCTTTC | p.Phe2733CysfsTer33 | frameshift_variant | Exon 43 of 44 | 1 | ENSP00000359655.3 | |||
PHF3 | ENST00000505138.1 | c.361+15256_361+15260delAGGAA | intron_variant | Intron 3 of 4 | 3 | ENSP00000421417.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152002Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000586 AC: 9AN: 153540Hom.: 0 AF XY: 0.0000982 AC XY: 8AN XY: 81444
GnomAD4 exome AF: 0.0000379 AC: 53AN: 1399046Hom.: 0 AF XY: 0.0000435 AC XY: 30AN XY: 690044
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152002Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74240
ClinVar
Submissions by phenotype
Retinitis pigmentosa 25 Pathogenic:6
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The EYS c.8133_8137delCTTTC; p.Phe2712fs variant (rs751629543), also known as c.8196_8200delCTTTC p.F2733Cfs*33 based on NM_001292009.1, is published in the medical literature in a family with autosomal recessive retinitis pigmentosa (Arai 2015). The variant is listed in the ClinVar database (Variation ID: 558163) and in the general population with an allele frequency of 0.006% (9/148188 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 5 nucleotides so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, this variant is predicted to cause loss of a critical functional domain (Hosono 2012). Considering available information, this variant is predicted to be pathogenic. References: Arai Y et al. Retinitis Pigmentosa with EYS Mutations Is the Most Prevalent Inherited Retinal Dystrophy in Japanese Populations. J Ophthalmol. 2015;2015:819760 Hosono K et al. Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population. PLoS One. 2012;7(2):e31036 -
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The EYS c.8133_8137del 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. Based on this evidence we have classified this variant as Pathogenic. -
Autosomal recessive retinitis pigmentosa Pathogenic:1
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not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Phe2712Cysfs*33) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 433 amino acid(s) of the EYS protein. This variant is present in population databases (rs751629543, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 26161267, 30153090). ClinVar contains an entry for this variant (Variation ID: 558163). This variant disrupts a region of the EYS protein in which other variant(s) (p.Thr3038Ilefs*4 and p.Asn3061Thrfs*3) have been determined to be pathogenic (PMID: 20333770, 21069908). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Retinal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at