13-48465116-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_000321.3(RB1):c.2325+5G>C variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000321.3 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.2325+5G>C | splice_donor_5th_base_variant, intron_variant | ENST00000267163.6 | |||
RB1 | NM_001407165.1 | c.2325+5G>C | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.2325+5G>C | splice_donor_5th_base_variant, intron_variant | 1 | NM_000321.3 | P1 | |||
RB1 | ENST00000643064.1 | c.194+83673G>C | intron_variant | ||||||
RB1 | ENST00000650461.1 | c.2325+5G>C | splice_donor_5th_base_variant, intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 28
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 28
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 02, 2023 | This sequence change falls in intron 22 of the RB1 gene. It does not directly change the encoded amino acid sequence of the RB1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with retinoblastoma (PMID: 20090211). This variant is also known as IVS 22+5 g.162115G>C. Variants that disrupt 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. This variant disrupts the c.2325+5G nucleotide in the RB1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 1662795, 16269091, 24225018). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.