rs587776788

Variant names:

• chr13-48380178-GACA-G
• rs587776788
• NM_000321.3:c.1439_1441delACA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000321.3(RB1):​c.1439_1441delACA​(p.Asn480del) variant causes a disruptive 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 (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: RB1 NM_000321.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.31
• Publications: 3 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 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, 13 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 rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1439_1441delACA	p.Asn480del	disruptive_inframe_deletion	Exon 16 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1439_1441delACA	p.Asn480del	disruptive_inframe_deletion	Exon 16 of 27		NP_001394094.1
RB1	NM_001407166.1	c.1439_1441delACA	p.Asn480del	disruptive_inframe_deletion	Exon 16 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1439_1441delACA	p.Asn480del	disruptive_inframe_deletion	Exon 16 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 30

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

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:3

Oct 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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:PM2, PS4SUP -

Sep 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects RB1 function (PMID: 9342358, 10486322). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 13091). This variant is also known as 1574del3. 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 is not present in population databases (gnomAD no frequency). 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 28, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587776788; hg19: chr13-48954314; COSMIC: COSV57334482;