13-48379594-C-T

Position:

• chr13-48379594-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000321.3(RB1):​c.1333C>T​(p.Arg445*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9045
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.30

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 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 13-48379594-C-T is Pathogenic according to our data. Variant chr13-48379594-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48379594-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1333C>T	p.Arg445*	stop_gained, splice_region_variant	14/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1333C>T	p.Arg445*	stop_gained, splice_region_variant	14/27		NP_001394094.1
RB1	NM_001407166.1	c.1333C>T	p.Arg445*	stop_gained, splice_region_variant	14/17		NP_001394095.1
LOC112268118	XR_002957522.2	n.40+241G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1333C>T	p.Arg445*	stop_gained, splice_region_variant	14/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1333C>T	p.Arg445*	stop_gained, splice_region_variant	14/27			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248914 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135036

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459970 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726232

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:4

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:9, UNILATERAL CASES:5, TOTAL CASES:14, PEDIGREES:14. ACMG Codes Applied:PVS1, PM2, PS4M -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 21, 1989	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 17, 2016	This is a nonsense alteration in which a C is replaced by a T at coding position 1333 and is predicted to change an Arginine at codon 445 to a premature stop codon. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Arg445*) 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 present in population databases (rs3092891, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 2594029, 20447117, 22328814, 22963398, 26787237). ClinVar contains an entry for this variant (Variation ID: 13071). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2022

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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 29261756, 34190019, 22328814, 26787237, 34294096, 2594029) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2024

The p.R445* pathogenic mutation (also known as c.1333C>T), located in coding exon 14 of the RB1 gene, results from a C to T substitution at nucleotide position 1333. This changes the amino acid from an arginine to a stop codon within coding exon 14. This mutation has been detected in multiple individuals with retinoblastoma (Yandell DW et al. N. Engl. J. Med., 1989 Dec;321:1689-95; Richter S et al. Am J Hum Genet, 2003 Feb;72:253-69; Abouzeid H et al. Mol. Vis., 2007 Sep;13:1740-5; Dommering CJ et al. Fam Cancer, 2012 Jun;11:225-33; Seo SH et al. Clin Genet, 2013 May;83:494-6; He MY et al. Mol Vis, 2014 Apr;20:545-52; Dommering CJ et al. J Med Genet, 2014 Jun;51:366-74; Niederst MJ et al. Nat Commun, 2015 Mar;6:6377; Sagi M et al. Fam Cancer, 2015 Sep;14:471-80; Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Meric-Bernstam F et al. Ann Oncol, 2016 05;27:795-800; Singh J et al. Mol Vis, 2016 Aug;22:1036-47; Shahraki K et al. Eye (Lond), 2017 Apr;31:620-627; Tomar S et al. PLoS ONE, 2017 Jun;12:e0178776; Parma D et al. PLoS ONE, 2017 Dec;12:e0189736; Chaussade A et al. Eur J Med Genet, 2019 Mar;62:217-223; Lan X et al. Front Genet, 2020 Mar;11:142; Gupta H et al. BMC Med Genomics, 2021 Jul;14:188). Of note, this alteration is also designated as 1462C>T in published literature. 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. -

Malignant tumor of urinary bladder;C0035335:Retinoblastoma;C0149925:Small cell lung carcinoma;C0585442:Bone osteosarcoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.97
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.030		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: rs3092891; hg19: chr13-48953730; COSMIC: COSV57295313; COSMIC: COSV57295313;