13-48456354-G-C

Position:

• chr13-48456354-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000321.3(RB1):​c.1960+5G>C variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.78

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48456354-G-C is Pathogenic according to our data. Variant chr13-48456354-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 428745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1960+5G>C		splice_region_variant, intron_variant		ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1960+5G>C		splice_region_variant, intron_variant			NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1960+5G>C		splice_region_variant, intron_variant		1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1960+5G>C		splice_region_variant, intron_variant				ENSP00000497193.1
RB1	ENST00000643064.1	c.192+74911G>C		intron_variant				ENSP00000496005.1
RB1	ENST00000480491.1	n.*47G>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 10, 2022

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 14769601, 29662154). ClinVar contains an entry for this variant (Variation ID: 428745). This variant is also known as g.153358G>C. This variant has been observed in individual(s) with retinoblastoma (PMID: 14769601, 29662154, 33493472; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 19 of the RB1 gene. It does not directly change the encoded amino acid sequence of the RB1 protein. It affects a nucleotide within the consensus splice site. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2015

The c.1960+5G>C intronic pathogenic mutation results from a G to C substitution 5 nucleotides after coding exon 19 in the RB1 gene. In one study, this alteration was identified in one individual with a clinical diagnosis of hereditary retinoblastoma. Further functional analysis demonstrated that this alteration abolishes the native donor splice site, leading to the skipping of coding exon 19, a frameshift, and a new premature stop codon in coding exon 20 (Tsai T, Arch. Ophthalmol. 2004 Feb; 122(2):239-48). Based on the available evidence, c.1960+5G>C is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.40		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs587778871; hg19: chr13-49030490; COSMIC: COSV57329378; COSMIC: COSV57329378;