rs1555285148

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000267163.6(RB1):​c.939+3A>T variant causes a splice donor region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RB1
ENST00000267163.6 splice_donor_region, intron

Scores

2
Splicing: ADA: 0.9999
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.61
Variant links:
Genes affected
RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RB1NM_000321.3 linkuse as main transcriptc.939+3A>T splice_donor_region_variant, intron_variant ENST00000267163.6 NP_000312.2
LOC112268118XR_002957522.2 linkuse as main transcriptn.124T>A splice_region_variant, non_coding_transcript_exon_variant 3/3
RB1NM_001407165.1 linkuse as main transcriptc.939+3A>T splice_donor_region_variant, intron_variant NP_001394094.1
RB1NM_001407166.1 linkuse as main transcriptc.939+3A>T splice_donor_region_variant, intron_variant NP_001394095.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RB1ENST00000267163.6 linkuse as main transcriptc.939+3A>T splice_donor_region_variant, intron_variant 1 NM_000321.3 ENSP00000267163 P1
RB1ENST00000650461.1 linkuse as main transcriptc.939+3A>T splice_donor_region_variant, intron_variant ENSP00000497193

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Retinoblastoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 27, 2019In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. This variant has been observed to segregate with retinoblastoma in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 527912). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 9 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.24
CADD
Benign
15
DANN
Benign
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.99
Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555285148; hg19: chr13-48939110; API