rs587776788
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000321.3(RB1):c.1439_1441del(p.Asn480del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D479D) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 30)
Consequence
RB1
NM_000321.3 inframe_deletion
NM_000321.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.31
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000321.3
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000321.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 13-48380178-GACA-G is Pathogenic according to our data. Variant chr13-48380178-GACA-G is described in ClinVar as [Pathogenic]. Clinvar id is 13091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1439_1441del | p.Asn480del | inframe_deletion | 16/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.1439_1441del | p.Asn480del | inframe_deletion | 16/27 | ||
RB1 | NM_001407166.1 | c.1439_1441del | p.Asn480del | inframe_deletion | 16/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1439_1441del | p.Asn480del | inframe_deletion | 16/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1439_1441del | p.Asn480del | inframe_deletion | 16/27 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinoblastoma Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1999 | - - |
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:3, UNILATERAL CASES:0, TOTAL CASES:3, PEDIGREES:3. ACMG Codes Applied:PM2, PS4SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2023 | This variant has been observed in individuals with unilateral or bilateral retinoblastoma (PMID: 1577465, 7927327, 12541220, 21520333; Invitae). It has also been observed to segregate with disease in related individuals. This variant, c.1439_1441del, results in the deletion of 1 amino acid(s) of the RB1 protein (p.Asn480del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant is also known as 1574del3. ClinVar contains an entry for this variant (Variation ID: 13091). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects RB1 function (PMID: 9342358, 10486322). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 28, 2023 | The c.1439_1441delACA pathogenic mutation (also known as p.N480del), located in coding exon 16 of the RB1 gene, results from an in-frame ACA deletion at nucleotide positions 1439 to 1441. This results in the deletion of an asparagine residue at amino acid position 480. This alteration affects the A/B pocket, a protein structural domain important for pRB function (DiCiommo D et al. Semin Cancer Biol, 2000 Aug;10:255-69). Functional studies have shown this variant to have a deleterious impact on protein function (Otterson GA et al. Am J Hum Genet, 1999 Oct;65(4):1040-6; Park Y et al. Cell Cycle, 2008 Aug;7(15):2384-91). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with RB1-related disease (Lohmann D et al. Hum Genet, 1992 Apr;89:49-53; Rodríguez-Martín C et al. J Hum Genet, 2020 Jan;65:165-174; Ambry internal data). Of note, this variant is also designated as Δ480, ΔAsn480, and delN480 in published literature. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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