chr13-48380178-GACA-G

Position:

• chr13-48380178-GACA-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

ACMG classification

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

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

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

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776788; hg19: chr13-48954314;