rs587778823

Positions:

• chr13-48303978-ACCG-A
• chr13-48303978-ACCG-ACCGCCG
• chr13-48303978-ACCG-ACCGCCGCCG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000321.3(RB1):​c.78_80delGCC​(p.Pro27del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 1,348,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.54

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]

RB1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 13-48303978-ACCG-A is Benign according to our data. Variant chr13-48303978-ACCG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410949.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr13-48303978-ACCG-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAdExome4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.78_80delGCC	p.Pro27del	disruptive_inframe_deletion	1/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.78_80delGCC	p.Pro27del	disruptive_inframe_deletion	1/27		NP_001394094.1
RB1	NM_001407166.1	c.78_80delGCC	p.Pro27del	disruptive_inframe_deletion	1/17		NP_001394095.1
RB1	NM_001407167.1	c.78_80delGCC	p.Pro27del	disruptive_inframe_deletion	1/3		NP_001394096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.78_80delGCC	p.Pro27del	disruptive_inframe_deletion	1/27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151892 Hom.: 0 Cov.: 32 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 AF: 0.0000430 AC: 58 AN: 1348762 Hom.: 0 AF XY: 0.0000391 AC XY: 26 AN XY: 665146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000382

Gnomad4 ASJ exome AF: 0.000126

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0000793

Gnomad4 FIN exome AF: 0.0000593

Gnomad4 NFE exome AF: 0.0000169

Gnomad4 OTH exome AF: 0.000160

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151892 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74186

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

Alfa AF: 0.000612 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinoblastoma Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This variant is an in-frame deletion of proline at codon 29 in the the RB1 protein. This deletion is in the contex of seven consectutive prolines from codon 23 to 29). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with unilateral retinoblastoma (ClinVar: SCV000087341.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	May 20, 2024	Case and Pedigree Information: BILATERAL CASES:0, UNILATERAL CASES:1, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PM2, BP3, BP6 -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs587778823; hg19: chr13-48878114;