13-48381295-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000321.3(RB1):​c.1547G>C​(p.Trp516Ser) variant causes a missense change involving the alteration of a 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. W516R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RB1
NM_000321.3 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RB1NM_000321.3 linkuse as main transcriptc.1547G>C p.Trp516Ser missense_variant 17/27 ENST00000267163.6
RB1NM_001407165.1 linkuse as main transcriptc.1547G>C p.Trp516Ser missense_variant 17/27
RB1NM_001407166.1 linkuse as main transcriptc.1547G>C p.Trp516Ser missense_variant 17/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RB1ENST00000267163.6 linkuse as main transcriptc.1547G>C p.Trp516Ser missense_variant 17/271 NM_000321.3 P1
RB1ENST00000650461.1 linkuse as main transcriptc.1547G>C p.Trp516Ser missense_variant 17/27
RB1ENST00000643064.1 linkuse as main transcriptc.47G>C p.Trp16Ser missense_variant 1/2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Retinoblastoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 14, 2023This variant is not present in population databases (gnomAD no frequency). 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 expected to disrupt RB1 protein function. ClinVar contains an entry for this variant (Variation ID: 458131). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 516 of the RB1 protein (p.Trp516Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.92
D;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Uncertain
0.79
D
MutationAssessor
Uncertain
2.5
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-11
D;.
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.91
MutPred
0.79
Gain of catalytic residue at L512 (P = 0.0054);Gain of catalytic residue at L512 (P = 0.0054);
MVP
0.98
MPC
1.7
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.98
gMVP
0.84

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555286687; hg19: chr13-48955431; API