13-48342717-A-T

Position:

• chr13-48342717-A-T

Variant summary

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

The NM_000321.3(RB1):​c.380+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 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_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.36

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48342717-A-T is Pathogenic according to our data. Variant chr13-48342717-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 527904.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.380+3A>T		splice_region_variant, intron_variant		ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.380+3A>T		splice_region_variant, intron_variant			NP_001394094.1
RB1	NM_001407166.1	c.380+3A>T		splice_region_variant, intron_variant			NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.380+3A>T		splice_region_variant, intron_variant		1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000467505.5	n.138-17300A>T		intron_variant		1		ENSP00000434702.1
RB1	ENST00000650461.1	c.380+3A>T		splice_region_variant, intron_variant				ENSP00000497193.1
RB1	ENST00000525036.1	n.542+3A>T		splice_region_variant, intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2018

For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). An experimental study has reported that this sequence change results in the skipping of exon 3 (PMID: 18181215). This variant has been reported to be de novo in an individual affected with bilateral retinoblastoma (Invitae). It has also been reported in individuals affected with bilateral retinoblastoma in the literature (PMID: 18181215) and the Leiden Open-source Variation Database (PMID: 21520333). This variant is also known as g.39564A>T IVS3+3 in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 3 of the RB1 gene. It does not directly change the encoded amino acid sequence of the RB1 protein, but it affects a nucleotide within the consensus splice site of the intron. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555282811; hg19: chr13-48916853;