NM_000321.3:c.1389+5G>A

Variant names:

• chr13-48379655-G-A
• rs1131690859
• NM_000321.3:c.1389+5G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000321.3(RB1):​c.1389+5G>A 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. 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_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.83

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 Likely_pathogenic. Variant got 8 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 13-48379655-G-A is Pathogenic according to our data. Variant chr13-48379655-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 428677.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1389+5G>A		splice_region_variant, intron_variant	Intron 14 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1389+5G>A		splice_region_variant, intron_variant	Intron 14 of 26		NP_001394094.1
RB1	NM_001407166.1	c.1389+5G>A		splice_region_variant, intron_variant	Intron 14 of 16		NP_001394095.1
LOC112268118	XR_002957522.2	n.40+180C>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+5G>A		splice_region_variant, intron_variant	Intron 14 of 26	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1389+5G>A		splice_region_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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 24, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1389+5G>A intronic pathogenic mutation (also known as g.76491G>A and IVS14+5G>A in some literature) results from a G to A substitution 5 nucleotides after coding exon 14 in the RB1 gene. This pathogenic mutation has been reported in several individuals affected with RB, and RT-PCR analyses have demonstrated that this mutation leads to exon 14 skipping (Alonso J et al. Hum. Mutat. 2001 May; 17(5):412-22; Houdayer C et al. Hum. Mutat. 2008 Jul; 29(7):975-82). 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_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		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: rs1131690859; hg19: chr13-48953791;