chr13-48303948-C-CGCCGCCGCT

Variant names:

• chr13-48303948-C-CGCCGCCGCT
• rs572454921
• NM_000321.3:c.45_53dupTGCCGCCGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000321.3(RB1):​c.45_53dupTGCCGCCGC​(p.Ala16_Ala18dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,357,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A18A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0430
• 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-DT (HGNC:42778): (RB1 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.45_53dupTGCCGCCGC	p.Ala16_Ala18dup	disruptive_inframe_insertion	Exon 1 of 27	ENST00000267163.6	NP_000312.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.45_53dupTGCCGCCGC	p.Ala16_Ala18dup	disruptive_inframe_insertion	Exon 1 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.37e-7 AC: 1 AN: 1357280 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 669570

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27772

American (AMR) AF: 0.00 AC: 0 AN: 33220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24184

East Asian (EAS) AF: 0.00 AC: 0 AN: 32406

South Asian (SAS) AF: 0.00 AC: 0 AN: 76574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4026

European-Non Finnish (NFE) AF: 9.36e-7 AC: 1 AN: 1068464

Other (OTH) AF: 0.00 AC: 0 AN: 56542

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:1

Mar 04, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with RB1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant, c.45_53dup, results in the insertion of 3 amino acid(s) to the RB1 protein (p.Ala16_Ala18dup), but otherwise preserves the integrity of the reading frame. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.45_53dupTGCCGCCGC variant (also known as p.A16_A18dup), located in coding exon 1 of the RB1 gene, results from an in-frame duplication of TGCCGCCGC at nucleotide positions 45 to 53. This results in the duplication of 3 extra residues (AAA) between codons 16 and 18. This amino acid region is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. -

Malignant tumor of urinary bladder;C0035335:Retinoblastoma;C0149925:Small cell lung carcinoma;C0585442:Bone osteosarcoma Uncertain:1

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.043

Splicing

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

Other links and lift over

dbSNP: rs572454921; hg19: chr13-48878084;