rs1555294626

chr13-48465328-GAAGG-GTTT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000321.3(RB1):c.2450_2453delinsTTT(p.Glu817ValfsTer9) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 28)
• Consequence: RB1 NM_000321.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.88

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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-48465329-AAGG-TTT is Pathogenic according to our data. Variant chr13-48465329-AAGG-TTT is described in ClinVar as [Pathogenic]. Clinvar id is 527909.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.2450_2453delinsTTT	p.Glu817ValfsTer9	frameshift_variant	23/27	ENST00000267163.6
RB1	NM_001407165.1	c.2450_2453delinsTTT	p.Glu817ValfsTer9	frameshift_variant	23/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.2450_2453delinsTTT	p.Glu817ValfsTer9	frameshift_variant	23/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.2450_2453delinsTTT	p.Glu817ValfsTer9	frameshift_variant	23/27
RB1	ENST00000643064.1	c.194+83886_194+83889delinsTTT		intron_variant

Frequencies

GnomAD3 genomes Cov.: 28

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

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 11, 2017

This sequence change creates a premature translational stop signal (p.Glu817Valfs*9) in the RB1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant has not been reported in the literature in individuals with RB1-related disease. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555294626; hg19: chr13-49039465;