chr6-63720626-A-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001142800.2(EYS):c.9405T>A(p.Tyr3135*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,354,866 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 Likely pathogenic (★★).
Frequency
Consequence
NM_001142800.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.9405T>A | p.Tyr3135* | stop_gained | Exon 43 of 43 | 5 | NM_001142800.2 | ENSP00000424243.1 | ||
EYS | ENST00000370621.7 | c.9468T>A | p.Tyr3156* | stop_gained | Exon 44 of 44 | 1 | ENSP00000359655.3 | |||
PHF3 | ENST00000262043.8 | c.*6918A>T | 3_prime_UTR_variant | Exon 16 of 16 | 5 | NM_001370348.2 | ENSP00000262043.4 | |||
PHF3 | ENST00000505138.1 | c.361+9264A>T | intron_variant | Intron 3 of 4 | 3 | ENSP00000421417.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000161 AC: 2AN: 124588Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 64614
GnomAD4 exome AF: 0.0000140 AC: 19AN: 1354866Hom.: 0 Cov.: 28 AF XY: 0.0000180 AC XY: 12AN XY: 665040
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Retinitis pigmentosa 25 Pathogenic:6
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not provided Pathogenic:5
This sequence change creates a premature translational stop signal (p.Tyr3135*) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the EYS protein. This variant is present in population databases (rs137853190, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with EYS-related conditions (PMID: 18976725, 29159838, 30337596, 31074760). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.9468T>A;p.Y3156X. ClinVar contains an entry for this variant (Variation ID: 538). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
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The Y3156X likely pathogenic variant in the EYS gene has been reported previously in the homozygous state in two unrelated families with autosomal recessive retinitis pigmentosa (Collin et al., 2008). This variant is predicted to cause loss of normal protein function through protein truncation. Furthermore, the Y3156X variant was not observed in approximately 2,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret Y3156X as a likely pathogenic variant -
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Retinal dystrophy Pathogenic:2
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EYS-related disorder Pathogenic:1
The EYS c.9405T>A variant is predicted to result in premature protein termination (p.Tyr3135*). This variant has been reported to be causative for autosomal recessive retinitis pigmentosa (Collin et al. 2008. PubMed ID: 18976725; Ezquerra-Inchausti et al. 2018. PubMed ID: 30337596; Messchaert et al. 2018. PubMed ID: 29159838). This variant is reported in 0.0050% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in EYS are expected to be pathogenic. This variant is interpreted as pathogenic. -
Retinitis pigmentosa Pathogenic:1
The p.Tyr3135Ter 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, PM3-P. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at