rs1555279518

Positions:

• chr13-48307405-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000321.3(RB1):​c.263T>G​(p.Leu88Trp) variant causes a missense, splice region 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. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense, splice_region
• Scores: Splicing: ADA: 0.0001947
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.564

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27589053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.263T>G	p.Leu88Trp	missense_variant, splice_region_variant	2/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.263T>G	p.Leu88Trp	missense_variant, splice_region_variant	2/27		NP_001394094.1
RB1	NM_001407166.1	c.263T>G	p.Leu88Trp	missense_variant, splice_region_variant	2/17		NP_001394095.1
RB1	NM_001407167.1	c.263T>G	p.Leu88Trp	missense_variant, splice_region_variant	2/3		NP_001394096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.263T>G	p.Leu88Trp	missense_variant, splice_region_variant	2/27	1	NM_000321.3	ENSP00000267163	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RB1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with tryptophan at codon 88 of the RB1 protein (p.Leu88Trp). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and tryptophan. -

Malignant tumor of urinary bladder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.44	T;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.096
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.55	N;.;.
MutationTaster	Benign	0.87	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N;.;.
REVEL	Benign	0.21
Sift	Benign	0.077	T;.;.
Sift4G	Uncertain	0.059	T;.;.
Polyphen		0.99	D;.;.
Vest4		0.52
MutPred		0.49		Gain of catalytic residue at V87 (P = 0.0034);Gain of catalytic residue at V87 (P = 0.0034);Gain of catalytic residue at V87 (P = 0.0034);
MVP		0.83
MPC		1.1
ClinPred		0.33	T
GERP RS		2.6
Varity_R		0.061
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555279518; hg19: chr13-48881541;