NM_000321.3:c.1389+1G>A

Variant names:

• chr13-48379651-G-A
• NM_000321.3:c.1389+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000321.3(RB1):​c.1389+1G>A 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: 30)
• 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: 7.94

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.020452099 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 13-48379651-G-A is Pathogenic according to our data. Variant chr13-48379651-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1771465.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.1389+1G>A		splice_donor_variant, intron_variant	Intron 14 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1389+1G>A		splice_donor_variant, intron_variant	Intron 14 of 26		NP_001394094.1
RB1	NM_001407166.1	c.1389+1G>A		splice_donor_variant, intron_variant	Intron 14 of 16		NP_001394095.1
LOC112268118	XR_002957522.2	n.40+184C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1389+1G>A		splice_donor_variant, intron_variant	Intron 14 of 26	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1389+1G>A		splice_donor_variant, intron_variant	Intron 14 of 26			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:1

May 20, 2024

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:1, TOTAL CASES:2, PEDIGREES:2. ACMG Codes Applied:PVS1, PM2 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 12, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1389+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the RB1 gene. This mutation was previously detected in an 18-month-old diagnosed with unilateral retinoblastoma; subsequent RNA studies showed that this alteration results in skipping of exon 14 (Houdayer C et al. Hum. Mutat. 2004 Feb;23:193-202; Houdayer C et al. Hum. Mutat. 2008 Jul;29:975-82). Of note, this mutation is also designated as IVS14+1G>A and g.76487G>A in published literature. In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		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: chr13-48953787; COSMIC: COSV99925881; COSMIC: COSV99925881;