rs121913298

chr13-48349012-T-A

Variant summary

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

The NM_000321.3(RB1):c.596T>A(p.Leu199Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.48

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48349012-T-A is Pathogenic according to our data. Variant chr13-48349012-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 376329.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-48349012-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.596T>A	p.Leu199Ter	stop_gained	6/27	ENST00000267163.6
RB1	NM_001407165.1	c.596T>A	p.Leu199Ter	stop_gained	6/27
RB1	NM_001407166.1	c.596T>A	p.Leu199Ter	stop_gained	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.596T>A	p.Leu199Ter	stop_gained	6/27	1	NM_000321.3	P1
RB1	ENST00000467505.5	c.138-11005T>A		intron_variant, NMD_transcript_variant		1
RB1	ENST00000650461.1	c.596T>A	p.Leu199Ter	stop_gained	6/27
RB1	ENST00000525036.1	n.758T>A		non_coding_transcript_exon_variant	6/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Jul 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 25, 2021	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 376329). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 25712084). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu199*) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	38
Dann	Uncertain	0.99
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A
Vest4		0.89
GERP RS		5.2

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: rs121913298; hg19: chr13-48923148; COSMIC: COSV57300700;