rs1554163929
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001142800.2(EYS):c.8678del(p.Asn2893MetfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
EYS
NM_001142800.2 frameshift
NM_001142800.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.06
Genes affected
EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
PHF3 (HGNC:8921): (PHD finger protein 3) This gene encodes a member of a PHD finger-containing gene family. This gene may function as a transcription factor and may be involved in glioblastomas development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 33 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-63721352-AT-A is Pathogenic according to our data. Variant chr6-63721352-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517188.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EYS | NM_001142800.2 | c.8678del | p.Asn2893MetfsTer25 | frameshift_variant | 43/43 | ENST00000503581.6 | NP_001136272.1 | |
PHF3 | NM_001370348.2 | c.*7647del | 3_prime_UTR_variant | 16/16 | ENST00000262043.8 | NP_001357277.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.8678del | p.Asn2893MetfsTer25 | frameshift_variant | 43/43 | 5 | NM_001142800.2 | ENSP00000424243 | A2 | |
EYS | ENST00000370621.7 | c.8741del | p.Asn2914MetfsTer25 | frameshift_variant | 44/44 | 1 | ENSP00000359655 | P2 | ||
PHF3 | ENST00000262043.8 | c.*7647del | 3_prime_UTR_variant | 16/16 | 5 | NM_001370348.2 | ENSP00000262043 | P1 | ||
PHF3 | ENST00000505138.1 | c.363+9993del | intron_variant | 3 | ENSP00000421417 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 27, 2017 | The p.Asn2893MetfsX25 (NM_001142800.1 c.8678delA) variant in EYS has not been pr eviously reported in individuals with retinitis pigmentosa. Data from large popu lation studies is of insufficient coverage at this location to assess the freque ncy of this variant. This variant is predicted to cause a frameshift, which alte rs the protein?s amino acid sequence beginning at position 2893 and leads to a p remature termination codon 25 amino acids downstream. This alteration is then pr edicted to lead to a truncated or absent protein. Biallelic loss of function of the EYS gene is an established disease mechanism in retinitis pigmentosa. In sum mary, although additional studies are required to fully establish its clinical s ignificance, the p.Asn2893MetfsX25 variant is likely pathogenic for retinitis pi gmentosa in an autosomal recessive manner based upon its predicted functional im pact. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at