rs587778844

chr13-48367574-TA-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.1024del(p.Thr342LeufsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.32

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]

LOC112268118 (HGNC:):

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 13-48367574-TA-T is Pathogenic according to our data. Variant chr13-48367574-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 126826.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-48367574-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.1024del	p.Thr342LeufsTer7	frameshift_variant	10/27	ENST00000267163.6
LOC112268118	XR_002957522.2	n.122-2599del		intron_variant, non_coding_transcript_variant
RB1	NM_001407165.1	c.1024del	p.Thr342LeufsTer7	frameshift_variant	10/27
RB1	NM_001407166.1	c.1024del	p.Thr342LeufsTer7	frameshift_variant	10/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.1024del	p.Thr342LeufsTer7	frameshift_variant	10/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.1024del	p.Thr342LeufsTer7	frameshift_variant	10/27

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

May 20, 2024

Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PVS1, PM2 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2016

The c.1024delA pathogenic mutation, located in coding exon 10 of the RB1 gene, results from a deletion of one nucleotide at nucleotide position 1024, causing a translational frameshift with a predicted alternate stop codon. This alteration has been detected in multiple individuals and families diagnosed with retinoblastoma (Houdayer C et al. Hum. Mutat. 2004 Feb;23(2):193-202; Taylor M et al. Hum. Mutat. 2007 Mar;28(3):284-93). In addition to the information presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587778844; hg19: chr13-48941710;