13-48379594-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. R445R) has been classified as Likely benign. 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

Publications

42 publications found

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 Gene-Disease associations (from GenCC):

hereditary retinoblastoma
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
retinoblastoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
melanoma
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

RB1 links:

LOC112268118 (HGNC:):

LOC112268118 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 VariationId is 13071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.1333C>T	p.Arg445*	stop_gained, splice_region_variant	Exon 14 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.1333C>T	p.Arg445*	stop_gained, splice_region_variant	Exon 14 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.1333C>T	p.Arg445*	stop_gained, splice_region_variant	Exon 14 of 17		NP_001394095.1
LOC112268118	XR_002957522.2 link	n.40+241G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.1333C>T	p.Arg445*	stop_gained, splice_region_variant	Exon 14 of 27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248914

AF XY:

0.00000741

show subpopulations

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 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:

AN:

1459970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726232

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39566

South Asian (SAS)

AF:

0.00

AC:

AN:

86048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5202

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111430

Other (OTH)

AF:

0.00

AC:

AN:

60254

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000541

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Pathogenic:4

May 20, 2024

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Case and Pedigree Information: BILATERAL CASES:9, UNILATERAL CASES:5, TOTAL CASES:14, PEDIGREES:14. ACMG Codes Applied:PVS1, PM2, PS4M -

Dec 21, 1989

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 17, 2016

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 29, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 25, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

PhyloP100

2.3

Vest4

0.97

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.90

dbscSNV1_RF

Pathogenic

0.73

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over