rs587778850

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000321.3(RB1):c.2520+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RB1
NM_000321.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 8.77

Publications

3 publications found

Variant links:

COSMIC-nc: COSV57294549

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]

RB1 Gene-Disease associations (from GenCC):

hereditary retinoblastoma
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
retinoblastoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
melanoma
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

RB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.011123071 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.5, offset of 39, new splice context is: attGTaagt. 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 13-48473391-G-A is Pathogenic according to our data. Variant chr13-48473391-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 126805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.2520+1G>A		splice_donor_variant, intron_variant	Intron 24 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1 link	c.2520+1G>A		splice_donor_variant, intron_variant	Intron 24 of 26		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.2520+1G>A		splice_donor_variant, intron_variant	Intron 24 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1409452

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703868

African (AFR)

AF:

0.00

AC:

AN:

32202

American (AMR)

AF:

0.00

AC:

AN:

44572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25780

East Asian (EAS)

AF:

0.00

AC:

AN:

39278

South Asian (SAS)

AF:

0.00

AC:

AN:

85138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52714

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5028

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1066154

Other (OTH)

AF:

0.00

AC:

AN:

58586

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Pathogenic:3

Apr 27, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2520+1G>A variant in RB1 has been reported in at least 2 individuals with retinoblastoma (Richter 2003, Houdayer 2008) and was absent from large populatio n studies. This variant occurs in the invariant region (+/- 1,2) of the splice c onsensus sequence and is predicted to cause altered splicing leading to an abnor mal or absent protein. However, this information is not predictive enough to det ermine pathogenicity. Functional analysis using patient cell lines demonstrated that the c.2520+1G>A variant results in skipping of exon 24 (Houdayer 2008, John son 2014). This results in a frameshift, which is predicted to lead to loss of function via nonsense mediated decay (NMD). Loss of function is an established mechanism of disease for the RB1 gene. In summary, this variant meets criteria to be classified as pathogenic for retinoblastoma in an autosomal dominant manne r. ACMG criteria applied: PVS1, PM2, PS4_Supporting.

May 20, 2024

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Case and Pedigree Information: BILATERAL CASES:3, UNILATERAL CASES:0, TOTAL CASES:3, PEDIGREES:3. ACMG Codes Applied:PVS1, PM2, PS4SUP

Oct 13, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 18000883). Disruption of this splice site has been observed in several individuals affected with retinoblastoma (PMID: 12541220, 18000883, 28193182, 16595082). This variant is also described as c.2658+1G>A and g.170403G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 126805). This sequence change affects a donor splice site in intron 24 of the RB1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

Hereditary cancer-predisposing syndrome

Pathogenic:1

Dec 03, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2520+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide(s) after coding exon 24 of the RB1 gene. This variant has been reported in individual(s) with features consistent with RB1-related hereditary retinoblastoma (Rodríguez-Martín C et al. J Hum Genet, 2020 Jan;65:165-174; Richter S et al. Am J Hum Genet, 2003 Feb;72:253-69; Tsai T et al. Arch Ophthalmol, 2004 Feb;122:239-48; Houdayer C et al. Hum Mutat, 2004 Feb;23:193-202; Ambry internal data). In multiple assays testing RB1 function, this variant showed functionally abnormal results (Gámez-Pozo A et al. Hum Mutat, 2007 Dec;28:1245; Johnson BE et al. Science, 2014 Jan;343:189-193; Houdayer C et al. Hum Mutat, 2008 Jul;29:975-82). Of note, this variant is also referred to as c.2658+1G>A and g.170403G>A in the literature. 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. 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.

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.0

.;.

MetaRNN

Benign

0.0

.;.

MutationAssessor

Benign

0.0

.;.

PhyloP100

8.8

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0

.;.

Vest4

0.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

Splicevardb

3.0

SpliceAI score (max)

0.76

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.76

Position offset: -1

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over