rs587776781

chr13-48465029-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000321.3(RB1):c.2244del(p.Glu748AspfsTer6) 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 (no stars). Synonymous variant affecting the same amino acid position (i.e. E748E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 28)
• Consequence: RB1 NM_000321.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.174

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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48465029-AG-A is Pathogenic according to our data. Variant chr13-48465029-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 13074.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48465029-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.2244del	p.Glu748AspfsTer6	frameshift_variant	22/27	ENST00000267163.6
RB1	NM_001407165.1	c.2244del	p.Glu748AspfsTer6	frameshift_variant	22/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.2244del	p.Glu748AspfsTer6	frameshift_variant	22/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.2244del	p.Glu748AspfsTer6	frameshift_variant	22/27
RB1	ENST00000643064.1	c.194+83587del		intron_variant

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinoblastoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 21, 1989

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs587776781; hg19: chr13-49039165; COSMIC: COSV57318507;