rs1555282792

Positions:

• chr13-48342677-T-C

Variant summary

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

The ENST00000267163.6(RB1):​c.343T>C​(p.Phe115Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F115F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 ENST00000267163.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09

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=0.41598094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.343T>C	p.Phe115Leu	missense_variant	3/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.343T>C	p.Phe115Leu	missense_variant	3/27		NP_001394094.1
RB1	NM_001407166.1	c.343T>C	p.Phe115Leu	missense_variant	3/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.343T>C	p.Phe115Leu	missense_variant	3/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000467505.5	c.138-17340T>C		intron_variant, NMD_transcript_variant		1		ENSP00000434702
RB1	ENST00000650461.1	c.343T>C	p.Phe115Leu	missense_variant	3/27			ENSP00000497193
RB1	ENST00000525036.1	n.505T>C		non_coding_transcript_exon_variant	3/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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 phenylalanine with leucine at codon 115 of the RB1 protein (p.Phe115Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.28
Sift	Benign	0.34	T;.
Sift4G	Benign	0.10	T;.
Polyphen		0.26	B;.
Vest4		0.85
MutPred		0.50		Gain of catalytic residue at L110 (P = 0.0011);Gain of catalytic residue at L110 (P = 0.0011);
MVP		0.78
MPC		1.4
ClinPred		0.95	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1555282792; hg19: chr13-48916813;