13-48465022-G-T

Variant names:

• chr13-48465022-G-T
• NM_000321.3:c.2236G>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000321.3(RB1):​c.2236G>T​(p.Glu746*) variant causes a stop gained change involving the alteration of a conserved nucleotide. 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: 𝑓 0.0 (0 hom., cov: 27)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.60

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-48465022-G-T is Pathogenic according to our data. Variant chr13-48465022-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1069507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48465022-G-T is described in Lovd as [Pathogenic]. Variant chr13-48465022-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.2236G>T	p.Glu746*	stop_gained	Exon 22 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2236G>T	p.Glu746*	stop_gained	Exon 22 of 27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2236G>T	p.Glu746*	stop_gained	Exon 22 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.2236G>T	p.Glu746*	stop_gained	Exon 22 of 27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+83579G>T		intron_variant	Intron 1 of 1			ENSP00000496005.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 119674 Hom.: 0 Cov.: 27 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.36e-7 AC: 1 AN: 1068314 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 538268

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000443

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 119674 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 55000

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:2

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:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PVS1, PM2 -

Jun 24, 2023

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.Glu746*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 12173465, 28193182, 30636860). This variant is also known as g.162021 G>T. ClinVar contains an entry for this variant (Variation ID: 1069507). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.95
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-49039158; COSMIC: COSV57314725;