rs1131690859

Positions:

• chr13-48379655-G-A
• chr13-48379655-G-C
• chr13-48379655-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The ENST00000267163.6(RB1):​c.1389+5G>A variant causes a splice donor 5th base, 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 ENST00000267163.6 splice_donor_5th_base, 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1389+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000267163.6	NP_000312.2
LOC112268118	XR_002957522.2	n.40+180C>T		intron_variant, non_coding_transcript_variant
RB1	NM_001407165.1	c.1389+5G>A		splice_donor_5th_base_variant, intron_variant			NP_001394094.1
RB1	NM_001407166.1	c.1389+5G>A		splice_donor_5th_base_variant, intron_variant			NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1389+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1	c.1389+5G>A		splice_donor_5th_base_variant, intron_variant				ENSP00000497193

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2018

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;