chr13-48380210-C-G

Position:

• chr13-48380210-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The ENST00000267163.6(RB1):​c.1467C>G​(p.Cys489Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C489Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RB1 ENST00000267163.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0680

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 21) in uniprot entity RB_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in ENST00000267163.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-48380209-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428699.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1467C>G	p.Cys489Trp	missense_variant	16/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1467C>G	p.Cys489Trp	missense_variant	16/27		NP_001394094.1
RB1	NM_001407166.1	c.1467C>G	p.Cys489Trp	missense_variant	16/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1467C>G	p.Cys489Trp	missense_variant	16/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1	c.1467C>G	p.Cys489Trp	missense_variant	16/27			ENSP00000497193

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Nov 19, 2020

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RB1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tryptophan at codon 489 of the RB1 protein (p.Cys489Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Benign	0.097
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-10	D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.74		Gain of catalytic residue at A488 (P = 0);Gain of catalytic residue at A488 (P = 0);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		-3.8
Varity_R		1.0
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-48954346;