13-48373424-C-T

Position:

• chr13-48373424-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.1147C>T​(p.Gln383Ter) 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, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.88

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 13-48373424-C-T is Pathogenic according to our data. Variant chr13-48373424-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 428664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48373424-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.1147C>T	p.Gln383Ter	stop_gained	12/27	ENST00000267163.6	NP_000312.2
LOC112268118	XR_002957522.2	n.121+736G>A		intron_variant, non_coding_transcript_variant
RB1	NM_001407165.1	c.1147C>T	p.Gln383Ter	stop_gained	12/27		NP_001394094.1
RB1	NM_001407166.1	c.1147C>T	p.Gln383Ter	stop_gained	12/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1147C>T	p.Gln383Ter	stop_gained	12/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1	c.1147C>T	p.Gln383Ter	stop_gained	12/27			ENSP00000497193

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2016

The p.Q383* pathogenic mutation (also known as c.1147C>T), located in coding exon 12 of the RB1 gene, results from a C to T substitution at nucleotide position 1147. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration has been reported in multiple individuals with bilateral retinoblastoma (Alonso J et al. Hum. Mutat., 2005 Jan;25:99; Richter S et al. Am. J. Hum. Genet., 2003 Feb;72:253-69). 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. -

RB1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2022

The RB1 c.1147C>T variant is predicted to result in premature protein termination (p.Gln383*). This variant has been reported in individuals with retinoblastoma (Table 1, Alonso et al. 2005. PubMed ID: 15605413; Table 3, Mosaic, Fang X et al 2021. PubMed ID: 34190019; Figure 1, Richter et al. 2003. PubMed ID: 12541220). It has also been reported as a somatic change in a retinoblastoma tumor specimen (Table 1, Kontic et al. 2006. PubMed ID: 16972022). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/428664/). Nonsense variants in RB1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A
Vest4		0.88
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: -19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1131690846; hg19: chr13-48947560; COSMIC: COSV57312613;