rs1131690901

Positions:

• chr13-48364896-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000267163.6(RB1):​c.869del​(p.Asn290MetfsTer11) 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 ENST00000267163.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.61

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 18 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 13-48364896-GA-G is Pathogenic according to our data. Variant chr13-48364896-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 428726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48364896-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.869del	p.Asn290MetfsTer11	frameshift_variant	9/27	ENST00000267163.6	NP_000312.2
LOC112268118	XR_002957522.2	n.201del		non_coding_transcript_exon_variant	3/3
RB1	NM_001407165.1	c.869del	p.Asn290MetfsTer11	frameshift_variant	9/27		NP_001394094.1
RB1	NM_001407166.1	c.869del	p.Asn290MetfsTer11	frameshift_variant	9/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.869del	p.Asn290MetfsTer11	frameshift_variant	9/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1	c.869del	p.Asn290MetfsTer11	frameshift_variant	9/27			ENSP00000497193

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1400408 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 691246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Labcorp Genetics (formerly Invitae), Labcorp

May 19, 2018

This variant has been observed in individuals affected with retinoblastoma (PMID: 24225018, 29261756). ClinVar contains an entry for this variant (Variation ID: 428726). This sequence change creates a premature translational stop signal (p.Asn290Metfs*11) 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). Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2016

The c.869delA pathogenic mutation, located in coding exon 9 of the RB1 gene, results from a deletion of one nucleotide at nucleotide position 869, causing a translational frameshift with a predicted alternate stop codon. This alteration has been reported in the literature in a cohort of retinoblastoma patients (Price EA et al. J. Med. Genet. 2014 Mar; 51(3):208-14). In addition to 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)		0.0		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: rs1131690901; hg19: chr13-48939032;