rs587776779

Positions:

• chr13-48473387-CG-C
• chr13-48473387-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000321.3(RB1):​c.2520+1delG variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.97

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: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.010764263 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.9, offset of 0 (no position change), new splice context is: cggGTgagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48473387-CG-C is Pathogenic according to our data. Variant chr13-48473387-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 13069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.2520+1delG		splice_donor_variant, intron_variant		ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2520+1delG		splice_donor_variant, intron_variant			NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2520+1delG		splice_donor_variant, intron_variant		1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.2520+1delG		splice_donor_variant, intron_variant				ENSP00000497193.1
RB1	ENST00000643064.1	c.192+91948delG		intron_variant				ENSP00000496005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1410152 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 704282

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:2

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:1, TOTAL CASES:2, PEDIGREES:2. ACMG Codes Applied:PVS1, PM2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 21, 1989	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2022

The c.2520+1delG intronic pathogenic mutation, located in intron 24 of the RB1 gene, results from a deletion of one nucleotide within intron 24 of the RB1 gene. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with RB1-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified 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: rs587776779; hg19: chr13-49047523;