rs1060503075

Positions:

• chr13-48463817-TCCTC-T

Variant summary

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

The NM_000321.3(RB1):​c.2194_2197del​(p.Pro732MetfsTer11) 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: 6.27

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 13-48463817-TCCTC-T is Pathogenic according to our data. Variant chr13-48463817-TCCTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 410922.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-48463817-TCCTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.2194_2197del	p.Pro732MetfsTer11	frameshift_variant	21/27	ENST00000267163.6
RB1	NM_001407165.1	c.2194_2197del	p.Pro732MetfsTer11	frameshift_variant	21/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.2194_2197del	p.Pro732MetfsTer11	frameshift_variant	21/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.2194_2197del	p.Pro732MetfsTer11	frameshift_variant	21/27
RB1	ENST00000643064.1	c.194+82375_194+82378del		intron_variant

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 21, 2016

This sequence change deletes 4 nucleotides from exon 21 of the RB1 mRNA (c.2194_2197delCCTC), causing a frameshift at codon 732. This creates a premature translational stop signal (p.Pro732Metfs*11) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in RB1 are known to be pathogenic (PMID: 17096365). 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

LitVar

Other links and lift over

dbSNP: rs1060503075; hg19: chr13-49037953;