rs587778862

Variant names:

• chr13-48307352-CAGAG-C
• NM_000321.3:c.217_220delAGAG

Your query was ambiguous. Multiple possible variants found:

• chr13-48307352-CAGAG-C
• chr13-48307352-CAGAG-CAG
• chr13-48307352-CAGAG-CAGAGAG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000321.3(RB1):​c.217_220delAGAG​(p.Arg73LeufsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.28

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48307352-CAGAG-C is Pathogenic according to our data. Variant chr13-48307352-CAGAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 2736015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-48307352-CAGAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.217_220delAGAG	p.Arg73LeufsTer3	frameshift_variant	Exon 2 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.217_220delAGAG	p.Arg73LeufsTer3	frameshift_variant	Exon 2 of 27		NP_001394094.1
RB1	NM_001407166.1	c.217_220delAGAG	p.Arg73LeufsTer3	frameshift_variant	Exon 2 of 17		NP_001394095.1
RB1	NM_001407167.1	c.217_220delAGAG	p.Arg73LeufsTer3	frameshift_variant	Exon 2 of 3		NP_001394096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.217_220delAGAG	p.Arg73LeufsTer3	frameshift_variant	Exon 2 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Pathogenic:1

Nov 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg73Leufs*3) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 11317357). This variant is also known as g.5503_5506del4 (E73fsX75). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-48881488;