rs1131690902

Variant names:

• chr13-48342715-G-A
• rs1131690902
• NM_000321.3:c.380+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-48342715-G-A
• chr13-48342715-G-C
• chr13-48342715-G-T

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.380+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000701 in 1,427,292 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.40
• Publications: 1 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: 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 13-48342715-G-A is Pathogenic according to our data. Variant chr13-48342715-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 428727.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.380+1G>A		splice_donor_variant, intron_variant	Intron 3 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.380+1G>A		splice_donor_variant, intron_variant	Intron 3 of 26		NP_001394094.1
RB1	NM_001407166.1	c.380+1G>A		splice_donor_variant, intron_variant	Intron 3 of 16		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.380+1G>A		splice_donor_variant, intron_variant	Intron 3 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427292 Hom.: 0 Cov.: 26 AF XY: 0.00000140 AC XY: 1 AN XY: 711992

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32720

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25880

East Asian (EAS) AF: 0.00 AC: 0 AN: 39426

South Asian (SAS) AF: 0.00 AC: 0 AN: 85438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1080984

Other (OTH) AF: 0.00 AC: 0 AN: 59290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:2

Apr 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 3 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 428727). Disruption of this splice site has been observed in individual(s) with bilateral retinoblastoma (PMID: 22963398). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the RB1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -

Aug 20, 2020

Genetics Program, Instituto Nacional de Cancer

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 27, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.380+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the RB1 gene. This mutation has been reported in multiple individuals with bilateral retinoblastoma (Seo SH et al. Clin. Genet. 2013 May; 83(5):494-6; Yilmaz S et al. Hum. Mutat. 1998 ; 12(6):434). Of note, this mutation has been reported as IVS3+1G>A in the published literature. In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		6.4
GERP RS		5.4
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)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs1131690902; hg19: chr13-48916851;