13-48303689-AGCCTCGCGGACGTGACGCCGCGG-A

Variant summary

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

The 13-48303689-AGCCTCGCGGACGTGACGCCGCGG-A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 624,244 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RB1-DT
NR_046414.2 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.72
Variant links:
Genes affected
RB1-DT (HGNC:42778): (RB1 divergent transcript)
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]

Genome browser will be placed here

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 UniProt
RB1-DTNR_046414.2 linkuse as main transcript non_coding_transcript_exon_variant 1/3
RB1NM_000321.3 linkuse as main transcript upstream_gene_variant ENST00000267163.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RB1ENST00000267163.6 linkuse as main transcript upstream_gene_variant 1 NM_000321.3 P1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152062
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000177
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000110
AC:
52
AN:
472064
Hom.:
0
AF XY:
0.0000856
AC XY:
21
AN XY:
245200
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000156
Gnomad4 OTH exome
AF:
0.0000781
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74404
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000177
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.000106

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinoblastoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 27, 2024This variant occurs in a non-coding region of the RB1 gene. It does not change the encoded amino acid sequence of the RB1 protein. This variant is present in population databases (rs36230211, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2443575). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 26, 2024Has not been previously published as pathogenic or benign to our knowledge; Located in a regulatory region; in the absence of functional studies, the actual effect of this sequence change is unknown -
RB1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 12, 2022The RB1 c.-221_-199del23 variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-48877825-AGCCTCGCGGACGTGACGCCGCGG-A). Of note, variants within the RB1 promoter region have been reported in individuals with retinooblastoma (e.g. Ottaviani et al. 2013. PubMed ID: 23301675; Taylor et al. 2007. PubMed ID: 17096365). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs36230211; hg19: chr13-48877825; API