chr13-48342611-C-T

Position:

• chr13-48342611-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.277C>T​(p.Gln93Ter) variant causes a stop gained 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q93Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.18

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 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 13-48342611-C-T is Pathogenic according to our data. Variant chr13-48342611-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48342611-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.277C>T	p.Gln93Ter	stop_gained	3/27	ENST00000267163.6
RB1	NM_001407165.1	c.277C>T	p.Gln93Ter	stop_gained	3/27
RB1	NM_001407166.1	c.277C>T	p.Gln93Ter	stop_gained	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.277C>T	p.Gln93Ter	stop_gained	3/27	1	NM_000321.3	P1
RB1	ENST00000467505.5	c.138-17406C>T		intron_variant, NMD_transcript_variant		1
RB1	ENST00000650461.1	c.277C>T	p.Gln93Ter	stop_gained	3/27
RB1	ENST00000525036.1	n.439C>T		non_coding_transcript_exon_variant	3/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 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); Observed in an individual with unilateral retinoblastoma in published literature (Parsam et al., 2009); This variant is associated with the following publications: (PMID: 25525159, 20090211, 21725359, 26981779) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2015

The p.Q93* pathogenic mutation (also known as c.277C>T), located in coding exon 3 of the RB1 gene, results from a C to T substitution at nucleotide position 277. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation was previously identified in one individual with unilateral retinoblastoma(ParsamVL, J. Genet. 2009 Dec; 88(4):517-27).In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Benign	0.64	D
MutationTaster	Benign	1.0	A
Vest4		0.95
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1131690915; hg19: chr13-48916747; COSMIC: COSV57299384; COSMIC: COSV57299384;