13-48453065-T-G

Position:

• chr13-48453065-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000321.3(RB1):​c.1768T>G​(p.Cys590Gly) variant causes a missense 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. 15/21 in silico tools predict 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:4
• Conservation: PhyloP100: 1.62

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16500545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1768T>G	p.Cys590Gly	missense_variant	18/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1768T>G	p.Cys590Gly	missense_variant	18/27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1768T>G	p.Cys590Gly	missense_variant	18/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1768T>G	p.Cys590Gly	missense_variant	18/27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+71622T>G		intron_variant				ENSP00000496005.1
RB1	ENST00000480491.1	n.467T>G		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 04, 2023	This missense variant replaces cysteine with glycine at codon 590 of the RB1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RB1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2022	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function. ClinVar contains an entry for this variant (Variation ID: 410944). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 590 of the RB1 protein (p.Cys590Gly). -

Malignant tumor of urinary bladder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 05, 2023

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2024

The p.C590G variant (also known as c.1768T>G), located in coding exon 18 of the RB1 gene, results from a T to G substitution at nucleotide position 1768. The cysteine at codon 590 is replaced by glycine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.080
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Uncertain	0.010	D
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.080	N;.
REVEL	Benign	0.28
Sift	Benign	0.51	T;.
Sift4G	Benign	0.077	T;.
Polyphen		0.0060	B;.
Vest4		0.20
MutPred		0.47		Gain of catalytic residue at N593 (P = 0.001);Gain of catalytic residue at N593 (P = 0.001);
MVP		0.91
MPC		0.57
ClinPred		0.34	T
GERP RS		5.8
Varity_R		0.11
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060503089; hg19: chr13-49027201;