chr13-48380051-A-G
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000321.3(RB1):c.1390-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000178 in 1,122,088 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 Likely pathogenic (★★).
Frequency
Consequence
NM_000321.3 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1390-2A>G | splice_acceptor_variant | ENST00000267163.6 | |||
RB1 | NM_001407165.1 | c.1390-2A>G | splice_acceptor_variant | ||||
RB1 | NM_001407166.1 | c.1390-2A>G | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1390-2A>G | splice_acceptor_variant | 1 | NM_000321.3 | P1 | |||
RB1 | ENST00000650461.1 | c.1390-2A>G | splice_acceptor_variant |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome AF: 0.00000178 AC: 2AN: 1122088Hom.: 0 Cov.: 21 AF XY: 0.00000179 AC XY: 1AN XY: 559710
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 07, 2018 | Variant summary: RB1 c.1390-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 29758 control chromosomes. c.1390-2A>G has been reported in the literature in one individual affected with Retinoblastoma. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Retinoblastoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2017 | For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant has been reported in individuals affected with retinoblastoma (PMID: 27155049, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 14 of the RB1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at