rs1555286236

Variant names:

• chr13-48376977-C-CT
• rs1555286236
• NM_000321.3:c.1278dupT

Variant summary

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

The NM_000321.3(RB1):​c.1278dupT​(p.Lys427fs) variant causes a frameshift, stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.00

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]

LOC112268118 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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 13-48376977-C-CT is Pathogenic according to our data. Variant chr13-48376977-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 458116.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1278dupT	p.Lys427fs	frameshift_variant, stop_gained	Exon 13 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1278dupT	p.Lys427fs	frameshift_variant, stop_gained	Exon 13 of 27		NP_001394094.1
RB1	NM_001407166.1	c.1278dupT	p.Lys427fs	frameshift_variant, stop_gained	Exon 13 of 17		NP_001394095.1
LOC112268118	XR_002957522.2	n.41-2738dupA		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1278dupT	p.Lys427fs	frameshift_variant, stop_gained	Exon 13 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1278dupT	p.Lys427fs	frameshift_variant, stop_gained	Exon 13 of 27			ENSP00000497193.1

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

Jan 09, 2017

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. While this particular variant has not been reported in the literature, loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This sequence change inserts 1 nucleotide in exon 13 of the RB1 mRNA (c.1278dupT). This creates a premature translational stop signal (p.Lys427*) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1555286236; hg19: chr13-48951113;