rs1131690885

Positions:

• chr13-48459733-TTCTG-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.2011_2014del​(p.Glu672ThrfsTer4) variant causes a frameshift change involving the alteration of a 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: 30)
• Consequence: RB1 NM_000321.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67

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 13-48459733-TTCTG-T is Pathogenic according to our data. Variant chr13-48459733-TTCTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 428707.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-48459733-TTCTG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.2011_2014del	p.Glu672ThrfsTer4	frameshift_variant	20/27	ENST00000267163.6
RB1	NM_001407165.1	c.2011_2014del	p.Glu672ThrfsTer4	frameshift_variant	20/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.2011_2014del	p.Glu672ThrfsTer4	frameshift_variant	20/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.2011_2014del	p.Glu672ThrfsTer4	frameshift_variant	20/27
RB1	ENST00000643064.1	c.194+78295_194+78298del		intron_variant

Frequencies

GnomAD3 genomes Cov.: 30

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

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2020

The c.2011_2014delTCTG pathogenic mutation, located in coding exon 20 of the RB1 gene, results from a deletion of 4 nucleotides at nucleotide positions 2011 to 2014, causing a translational frameshift with a predicted alternate stop codon (p.E672Tfs*4). This mutation has been reported in an individual diagnosed with unilateral RB and retinoma in the other eye at 1 year-of-age. This mutation was noted to segregate with disease within this family as this individual had two children affected with bilateral RB. Of note, authors referred to this mutation as g.156743delTCTG and p.675X (Abouzeid H et al. Mol Vis. 2009;15:771-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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: rs1131690885; hg19: chr13-49033869;