chr13-48373493-G-C

Variant names:

• chr13-48373493-G-C
• NM_000321.3:c.1215+1G>C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000321.3(RB1):​c.1215+1G>C variant causes a splice donor, 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.39

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]

LOC112268118 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48373493-G-C is Pathogenic according to our data. Variant chr13-48373493-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2585720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1215+1G>C		splice_donor_variant, intron_variant	Intron 12 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1215+1G>C		splice_donor_variant, intron_variant	Intron 12 of 26		NP_001394094.1
RB1	NM_001407166.1	c.1215+1G>C		splice_donor_variant, intron_variant	Intron 12 of 16		NP_001394095.1
LOC112268118	XR_002957522.2	n.121+667C>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1215+1G>C		splice_donor_variant, intron_variant	Intron 12 of 26	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1215+1G>C		splice_donor_variant, intron_variant	Intron 12 of 26			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 23, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1215+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 12 of the RB1 gene. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with RB1-related disease (Ambry internal data; Rodríguez-Martín C et al. J Hum Genet, 2020 Jan;65:165-174). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

RB1-related disorder Pathogenic:1

Dec 27, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RB1 c.1215+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in RB1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-48947629; COSMIC: COSV57294684;