Variant 13-48303689-AGCCTCGCGGACGTGACGCCGCGG-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000433480.3(RB1-DT):n.-10_13delCCGCGGCGTCACGTCCGCGAGGC 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
ENST00000433480.3 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-DT links:

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]

RB1 links:

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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 rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.-223_-201delGCCTCGCGGACGTGACGCCGCGG		upstream_gene_variant		ENST00000267163.6	NP_000312.2	P06400A0A024RDV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.-223_-201delGCCTCGCGGACGTGACGCCGCGG		upstream_gene_variant		1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152062

Hom.:

Cov.:

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:

AN:

472064

Hom.:

AF XY:

0.0000856

AC XY:

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:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

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.:

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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2025

This 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. 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 submitter

clinical testing

GeneDx

Sep 26, 2024

Has 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 submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2022

The 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over