rs1461382798
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate
The NM_000321.3(RB1):c.1422-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,415,758 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
Consequence
NM_000321.3 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1422-1G>A | splice_acceptor_variant | ENST00000267163.6 | |||
RB1 | NM_001407165.1 | c.1422-1G>A | splice_acceptor_variant | ||||
RB1 | NM_001407166.1 | c.1422-1G>A | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1422-1G>A | splice_acceptor_variant | 1 | NM_000321.3 | P1 | |||
RB1 | ENST00000650461.1 | c.1422-1G>A | splice_acceptor_variant |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD4 exome AF: 7.06e-7 AC: 1AN: 1415758Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1AN XY: 702940
GnomAD4 genome ? Cov.: 30
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2021 | 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). 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. This variant has been reported in individuals affected with bilateral retinoblastoma (PMID: 15884040, Invitae). This variant is also known as c.1560-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 527931). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 15 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