Variant chr13-48367512-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000321.3(RB1):c.958C>T(p.Arg320Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,222 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RB1
NM_000321.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.08

Variant links:

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 links:

LOC112268118 (HGNC:):

LOC112268118 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 13-48367512-C-T is Pathogenic according to our data. Variant chr13-48367512-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 126824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48367512-C-T is described in Lovd as [Pathogenic]. Variant chr13-48367512-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RB1	NM_000321.3 linkuse as main transcript	c.958C>T	p.Arg320Ter	stop_gained	10/27	ENST00000267163.6	NP_000312.2
LOC112268118	XR_002957522.2 linkuse as main transcript	n.122-2536G>A		intron_variant, non_coding_transcript_variant
RB1	NM_001407165.1 linkuse as main transcript	c.958C>T	p.Arg320Ter	stop_gained	10/27		NP_001394094.1
RB1	NM_001407166.1 linkuse as main transcript	c.958C>T	p.Arg320Ter	stop_gained	10/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 linkuse as main transcript	c.958C>T	p.Arg320Ter	stop_gained	10/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1 linkuse as main transcript	c.958C>T	p.Arg320Ter	stop_gained	10/27			ENSP00000497193

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451222

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721618

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2023	This sequence change creates a premature translational stop signal (p.Arg320*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with bilateral retinoblastoma and retinoblastoma (PMID: 7704558, 12541220, 15605413, 24225018, 24810223, 25754945, 28575107). In at least one individual the variant was observed to be de novo. This variant is also known as g.64348C>T. ClinVar contains an entry for this variant (Variation ID: 126824). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Jul 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	May 20, 2024	Case and Pedigree Information: BILATERAL CASES:20, UNILATERAL CASES:2, TOTAL CASES:22, PEDIGREES:22. ACMG Codes Applied:PVS1, PM2, PS4S -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 22, 2023	The RB1 c.958C>T variant is classified as pathogenic (PVS1, PM6, PS4, PM2, PM3) The RB1 c.958C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 320 (PVS1). This variant has been identified as a de novo variant in at least four unrelated patients (PMID:33456302) (PM6). The variant has been widely reported in patients with retinoblastoma, both as germline, somatic and mosaic(PMID:33456302, PMID:28575107) (PS4). This variant is absent from population databases (PM2). This variant has been detected in trans with a somatic pathogenic variant (PMID:28575107) (PM3). The variant has been reported in dbSNP (rs121913300) and in the HGMD database as disease causing (CM941205). It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 126824) and in the RB1 variant database (LOVD RB1-000072). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2023

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Observed in multiple individuals with retinoblastoma (Lohmann et al., 1996; Choy et al., 2002; Alonso et al., 2005; Sagi et al., 2015; Tomar et al., 2017); This variant is associated with the following publications: (PMID: 19280657, 34190019, 8651278, 12402348, 33493472, 7704558, 28575107, 25754945, 12541220, 15605413, 27983729, 14722923, 18840911, 34308366, 34294096, 33456302, 31772335, 34277001, 34645364, 35960463, 33318192) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2021

The p.R320* pathogenic mutation (also known as c.958C>T), located in coding exon 10 of the RB1 gene, results from a C to T substitution at nucleotide position 958. This changes the amino acid from an arginine to a stop codon within coding exon 10. This mutation has been reported in numerous individuals affected with sporadic and familial retinoblastoma both bilaterally and unilaterally (Lohmann DR et al. Am. J. Hum. Genet. 1996 May;58(5):940-9; Richter S et al. Am. J. Hum. Genet. 2003 Feb;72(2):253-69; Alonso J et al. Hum. Mutat. 2005 Jan;25(1):99; Choy KW et al. Hum. Mutat. 2002 Nov;20(5):408; Houdayer C et al. Hum. Mutat. 2004 Feb; 23(2):193-202). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.83

MutationTaster

Benign

1.0

Vest4

0.96

GERP RS

5.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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