rs1131690858

Variant names:

• chr13-48473390-GGTGA-G
• rs1131690858
• NM_000321.3:c.2520+3_2520+6delGAGT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000321.3(RB1):​c.2520+3_2520+6delGAGT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.77
• Publications: 2 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-48473390-GGTGA-G is Pathogenic according to our data. Variant chr13-48473390-GGTGA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428676.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	c.2520+3_2520+6delGAGT		splice_region_variant, intron_variant	Intron 24 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2520+3_2520+6delGAGT		splice_region_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	c.2520+1_2520+4delGTGA		splice_donor_variant, splice_region_variant, intron_variant	Intron 24 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:2

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 24 of the RB1 gene. It does not directly change the encoded amino acid sequence of the RB1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with retinoblastoma (PMID: 7881418, 8605116, 25754945). In at least one individual the variant was observed to be de novo. This variant is also known as IVS24+3del4. ClinVar contains an entry for this variant (Variation ID: 428676). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

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:4, UNILATERAL CASES:0, TOTAL CASES:4, PEDIGREES:4. ACMG Codes Applied:PM2, PS4SUP -

not provided Pathogenic:1

Oct 06, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing and patient-derived cDNA analysis indicates skipping of exon 24 (Houdayer et al., 2008); This variant is associated with the following publications: (PMID: 8346255, 12541220, 18449911, 34247193, 7881418, 34277001, 8605116, 25754945, 24249257, 37602348) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 18, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2520+3_2520+6delGAGT intronic pathogenic mutation, located in intron 24 of the RB1 gene, results from a deletion of 4 nucleotides within intron 24 of the RB1 gene. This pathogenic mutation has been reported in the germline of multiple individuals diagnosed with sporadic or hereditary retinoblastoma (RB) (Ambry internal data; Lohmann DR et al. Hum. Mol. Genet. 1994 Dec;3:2187-93; Liu Z et al. Genes Chromosomes Cancer. 1995 Dec;14:277-84; Sagi M et al. Fam. Cancer. 2015 Sep;14:471-80). This pathogenic mutation has also been detected in the tumor of an individual with unilateral RB (Hogg A et al. Proc. Natl. Acad. Sci. U.S.A. 1993 Aug;90:7351-5). In addition this mutation leads to the skipping of exon 24 (Ambry internal data; Houdayer et al. Hum Mutat. 2008;29(7):975-82). Of note, this alteration is also designated as g.170405del4 and IVS24+3del4 in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary retinoblastoma Pathogenic:1

Jun 26, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		Position offset: 0

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

Other links and lift over

dbSNP: rs1131690858; hg19: chr13-49047526; COSMIC: COSV57302156; COSMIC: COSV57302156;