rs1555286250

Positions:

• chr13-48377034-G-A
• chr13-48377034-G-C
• chr13-48377034-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000321.3(RB1):​c.1332G>A​(p.Gln444=) variant causes a splice region, synonymous change. 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.95

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 14 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 13-48377034-G-A is Pathogenic according to our data. Variant chr13-48377034-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1071425.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.1332G>A	p.Gln444=	splice_region_variant, synonymous_variant	13/27	ENST00000267163.6	NP_000312.2
LOC112268118	XR_002957522.2	n.41-2794C>T		intron_variant, non_coding_transcript_variant
RB1	NM_001407165.1	c.1332G>A	p.Gln444=	splice_region_variant, synonymous_variant	13/27		NP_001394094.1
RB1	NM_001407166.1	c.1332G>A	p.Gln444=	splice_region_variant, synonymous_variant	13/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1332G>A	p.Gln444=	splice_region_variant, synonymous_variant	13/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1	c.1332G>A	p.Gln444=	splice_region_variant, synonymous_variant	13/27			ENSP00000497193

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: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:2, UNILATERAL CASES:1, TOTAL CASES:3, PEDIGREES:3. ACMG Codes Applied:PVS1, PM2, PS4SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 01, 2020	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1332 nucleotide in the RB1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18181215, 21520333). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 10882758). This variant has been observed in individual(s) with retinoblastoma (PMID: 10882758, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 444 of the RB1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RB1 protein. This variant also falls at the last nucleotide of exon 13 of the RB1 coding sequence, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-48951170; COSMIC: COSV57315055; COSMIC: COSV57315055;