rs1131690908

Positions:

• chr13-48473383-C-A
• chr13-48473383-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000267163.6(RB1):​c.2513C>A​(p.Ser838Ter) 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 ENST00000267163.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:1
• Conservation: PhyloP100: 6.90

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 12 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 13-48473383-C-A is Pathogenic according to our data. Variant chr13-48473383-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 428735.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.2513C>A	p.Ser838Ter	stop_gained	24/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2513C>A	p.Ser838Ter	stop_gained	24/27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2513C>A	p.Ser838Ter	stop_gained	24/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1	c.2513C>A	p.Ser838Ter	stop_gained	24/27			ENSP00000497193
RB1	ENST00000643064.1	c.194+91940C>A		intron_variant				ENSP00000496005

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1414668 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 706334

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

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

Jun 20, 2016

The p.S838* pathogenic mutation (also known as c.2513C>A), located in coding exon 24 of the RB1 gene, results from a C to A substitution at nucleotide position 2513. This changes the amino acid from a serine to a stop codon within coding exon 24. This alteration has previously been reported in an individual with familial retinoblastoma (Liu Z et al. Genes Chromosomes Cancer 1995 Dec;14(4):277-84). 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	0.65
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A
Vest4		0.97
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1131690908; hg19: chr13-49047519; COSMIC: COSV57298758; COSMIC: COSV57298758;