rs587778862

Variant names:

• chr13-48307352-CAGAG-C
• rs587778862
• NM_000321.3:c.217_220delAGAG

Your query was ambiguous. Multiple possible variants found:

• chr13-48307352-CAGAG-C
• chr13-48307352-CAGAG-CAG
• chr13-48307352-CAGAG-CAGAGAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000321.3(RB1):​c.217_220delAGAG​(p.Arg73LeufsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R73R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 4.28
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hereditary retinoblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 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 13-48307352-CAGAG-C is Pathogenic according to our data. Variant chr13-48307352-CAGAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2736015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.217_220delAGAG	p.Arg73LeufsTer3	frameshift	Exon 2 of 27	NP_000312.2
	RB1	NM_001407165.1		c.217_220delAGAG	p.Arg73LeufsTer3	frameshift	Exon 2 of 27	NP_001394094.1
	RB1	NM_001407166.1		c.217_220delAGAG	p.Arg73LeufsTer3	frameshift	Exon 2 of 17	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.217_220delAGAG	p.Arg73LeufsTer3	frameshift	Exon 2 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.137+3310_137+3313delAGAG		intron	N/A	ENSP00000434702.1
	RB1	ENST00000924352.1		c.217_220delAGAG	p.Arg73LeufsTer3	frameshift	Exon 2 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

View on ClinVar

Computational scores

Other links and lift over

dbSNP: rs587778862; hg19: chr13-48881488; COSMIC: COSV104565166;