rs1555279212

Positions:

• chr13-48303958-G-GCCGCCGCGGAACCCCCGGCA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000267163.6(RB1):​c.54_73dup​(p.Pro25ArgfsTer47) variant causes a frameshift change involving the alteration of a non-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. A16A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 ENST00000267163.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.51

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 581 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48303958-G-GCCGCCGCGGAACCCCCGGCA is Pathogenic according to our data. Variant chr13-48303958-G-GCCGCCGCGGAACCCCCGGCA is described in ClinVar as [Pathogenic]. Clinvar id is 458171.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.54_73dup	p.Pro25ArgfsTer47	frameshift_variant	1/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.54_73dup	p.Pro25ArgfsTer47	frameshift_variant	1/27		NP_001394094.1
RB1	NM_001407166.1	c.54_73dup	p.Pro25ArgfsTer47	frameshift_variant	1/17		NP_001394095.1
RB1	NM_001407167.1	c.54_73dup	p.Pro25ArgfsTer47	frameshift_variant	1/3		NP_001394096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.54_73dup	p.Pro25ArgfsTer47	frameshift_variant	1/27	1	NM_000321.3	ENSP00000267163	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 21, 2017

This sequence change creates a premature translational stop signal (p.Pro25Argfs*47) in the RB1 gene. It is expected to result in an absent or disrupted protein product. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant has been reported in an individual affected with retinoblastoma (PMID: 24688104). This variant is also referred to as c.46_65dup20 in the literature. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555279212; hg19: chr13-48878094;