6-64813377-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_001142800.2(EYS):c.3443+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.00000649 in 1,386,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000065 ( 0 hom. )
Consequence
EYS
NM_001142800.2 splice_donor
NM_001142800.2 splice_donor
Scores
2
4
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.76
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 10, offset of 22, new splice context is: caaGTaagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 6-64813377-C-T is Pathogenic according to our data. Variant chr6-64813377-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1069772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64813377-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYS | NM_001142800.2 | c.3443+1G>A | splice_donor_variant | ENST00000503581.6 | |||
EYS | NM_001292009.2 | c.3443+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.3443+1G>A | splice_donor_variant | 5 | NM_001142800.2 | A2 | |||
EYS | ENST00000370621.7 | c.3443+1G>A | splice_donor_variant | 1 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000137 AC: 2AN: 146414Hom.: 0 AF XY: 0.0000128 AC XY: 1AN XY: 77882
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GnomAD4 exome AF: 0.00000649 AC: 9AN: 1386652Hom.: 0 Cov.: 30 AF XY: 0.00000732 AC XY: 5AN XY: 683394
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa 25 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 21, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 28, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change affects a donor splice site in intron 22 of the EYS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (no rsID available, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with retinitis pigmentosa (PMID: 20237254, 25097241, 26667666). ClinVar contains an entry for this variant (Variation ID: 1069772). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -21
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at