13-48463730-G-C

Variant names:

• chr13-48463730-G-C
• rs587778860
• NM_000321.3:c.2107-1G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000321.3(RB1):​c.2107-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RB1 NM_000321.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.37
• Publications: 5 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03767492 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48463730-G-C is Pathogenic according to our data. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-48463730-G-C is described in CliVar as Pathogenic. Clinvar id is 126795.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.2107-1G>C		splice_acceptor_variant, intron_variant	Intron 20 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2107-1G>C		splice_acceptor_variant, intron_variant	Intron 20 of 26		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2107-1G>C		splice_acceptor_variant, intron_variant	Intron 20 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinoblastoma Pathogenic:1

Sep 16, 2013

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.4
GERP RS		6.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs587778860; hg19: chr13-49037866; COSMIC: COSV57304025;