rs1555282792

Variant names:

• chr13-48342677-T-C
• rs1555282792
• NM_000321.3:c.343T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-48342677-T-C
• chr13-48342677-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.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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.343T>C	p.Phe115Leu	missense_variant	Exon 3 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.343T>C	p.Phe115Leu	missense_variant	Exon 3 of 27		NP_001394094.1
RB1	NM_001407166.1	c.343T>C	p.Phe115Leu	missense_variant	Exon 3 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.343T>C	p.Phe115Leu	missense_variant	Exon 3 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000467505.5	n.138-17340T>C		intron_variant	Intron 1 of 2	1		ENSP00000434702.1
RB1	ENST00000650461.1	c.343T>C	p.Phe115Leu	missense_variant	Exon 3 of 27			ENSP00000497193.1
RB1	ENST00000525036.1	n.505T>C		non_coding_transcript_exon_variant	Exon 3 of 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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:1

Jul 19, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RB1-related disease. 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"). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F115L variant (also known as c.343T>C), located in coding exon 3 of the RB1 gene, results from a T to C substitution at nucleotide position 343. The phenylalanine at codon 115 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

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;.
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;