rs886042249

Positions:

• chr13-48465116-G-A
• chr13-48465116-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000321.3(RB1):​c.2325+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 28)
• Consequence: RB1 NM_000321.3 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.33

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-48465116-G-A is Pathogenic according to our data. Variant chr13-48465116-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281863.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.2325+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2325+5G>A		splice_donor_5th_base_variant, intron_variant			NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2325+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000643064.1	c.194+83673G>A		intron_variant				ENSP00000496005
RB1	ENST00000650461.1	c.2325+5G>A		splice_donor_5th_base_variant, intron_variant				ENSP00000497193

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 28

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2018

The c.2325+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 22 in the RB1 gene. This mutation has been reported in two unrelated individuals diagnosed with retinoblastoma and it was suggested that this alteration could possibly be a low penetrance allele (Price EA et al. J Med Genet. 2014 Mar;51(3):208-14; Valverde JR et al. BMC Genet. 2005 Nov 4;6:53). In addition, a similar alteration, c.2325+5G>C (referred to as IVS22+5G>C), has been reported in a proband with unilateral retinoblastoma, a sibling with bilateral retinoblastoma, and their unaffected mother. The authors concluded this was due to variable expressivity and incomplete penetrance (Parsam VL et al. J Genet. 2009 Dec;88(4):517-27). Based on the available evidence, c.2325+5G>A is classified as a pathogenic mutation. -

Retinoblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

May 20, 2024

Case and Pedigree Information: BILATERAL CASES:0, UNILATERAL CASES:1, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PM2, PP3 -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 15, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: 6
DS_DL_spliceai		0.88		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886042249; hg19: chr13-49039252;