chr13-48377030-C-A

Variant names:

• chr13-48377030-C-A
• rs1060503079
• NM_000321.3:c.1328C>A

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.1328C>A​(p.Ser443*) 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 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: 0.783

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 13-48377030-C-A is Pathogenic according to our data. Variant chr13-48377030-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 410927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48377030-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1328C>A	p.Ser443*	stop_gained	Exon 13 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1328C>A	p.Ser443*	stop_gained	Exon 13 of 27		NP_001394094.1
RB1	NM_001407166.1	c.1328C>A	p.Ser443*	stop_gained	Exon 13 of 17		NP_001394095.1
LOC112268118	XR_002957522.2	n.41-2790G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1328C>A	p.Ser443*	stop_gained	Exon 13 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1328C>A	p.Ser443*	stop_gained	Exon 13 of 27			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:1

Nov 16, 2016

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 at codon 443 (p.Ser443*) of the RB1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RB1 are known to be pathogenic. This particular variant has been reported in the literature in an individual with retinoblastoma (PMID: 12541220). -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 30, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S443* pathogenic mutation (also known as c.1328C>A) located in coding exon 13 of the RB1 gene, results from a C to A substitution at nucleotide position 1328. This changes the amino acid from a serine to a stop codon within coding exon 13. This alteration was previously identified in an individual with bilateral retinoblastoma (Richter S, Am. J. Hum. Genet. 2003 Feb; 72(2):253-69). 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	Uncertain	0.63
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.93
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060503079; hg19: chr13-48951166; COSMIC: COSV57294594; COSMIC: COSV57294594;