rs1131690895
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The ENST00000267163.6(RB1):c.607+1_607+2insT variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
ENST00000267163.6 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.607+2dupT | splice_region_variant, intron_variant | Intron 6 of 26 | ENST00000267163.6 | NP_000312.2 | ||
RB1 | NM_001407165.1 | c.607+2dupT | splice_region_variant, intron_variant | Intron 6 of 26 | NP_001394094.1 | |||
RB1 | NM_001407166.1 | c.607+2dupT | splice_region_variant, intron_variant | Intron 6 of 16 | NP_001394095.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.607+1_607+2insT | splice_donor_variant, intron_variant | Intron 6 of 26 | 1 | NM_000321.3 | ENSP00000267163.4 | |||
RB1 | ENST00000467505.5 | n.138-10993_138-10992insT | intron_variant | Intron 1 of 2 | 1 | ENSP00000434702.1 | ||||
RB1 | ENST00000650461.1 | c.607+1_607+2insT | splice_donor_variant, intron_variant | Intron 6 of 26 | ENSP00000497193.1 | |||||
RB1 | ENST00000525036.1 | n.769+1_769+2insT | splice_donor_variant, intron_variant | Intron 6 of 6 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1442952Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1AN XY: 717874
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:1
This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 6 of the RB1 gene. It does not directly change the encoded amino acid sequence of the RB1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant has been observed to be de novo in an individual affected with retinoblastoma (Invitae). ClinVar contains an entry for this variant (Variation ID: 428720). For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.607+2dupT intronic variant, results from a duplication of two nucleotides at nucleotide position 607 after intron 6 of the RB1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant has been observed in at least one individual with a personal and/or family history that is consistent with RB1-associated disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at