rs1060503088

chr13-48452981-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_000321.3(RB1):c.1696-12T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:1
• Conservation: PhyloP100: 1.66

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-48452981-T-G is Pathogenic according to our data. Variant chr13-48452981-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 410940.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.1696-12T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000267163.6
RB1	NM_001407165.1	c.1696-12T>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.1696-12T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000321.3	P1
RB1	ENST00000643064.1	c.194+71538T>G		intron_variant
RB1	ENST00000650461.1	c.1696-12T>G		splice_polypyrimidine_tract_variant, intron_variant
RB1	ENST00000480491.1	n.395-12T>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2016

For these reasons, this variant has been classified as Pathogenic. Experimental studies have reported that this variant creates a cryptic acceptor site in intron 17, which inserts 11 nucleotides of intronic sequence into the transcript, resulting in a frameshift and a premature truncation (PMID: 18181215). This variant has been reported in individuals affected with bilateral retinoblastoma (PMID: 18181215, 21520333, Invitae Database). In one of these individuals, family studies indicate this variant likely was not inherited from either parent (i.e. occurred de novo) (Invitae database). This variant is also known as IVS17-12 T>G in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 17 of the RB1 mRNA. It does not directly change the encoded amino acid sequence of the RB1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	22
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: 1
DS_AL_spliceai		0.96		Position offset: 12

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060503088; hg19: chr13-49027117;