13-48380232-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000321.3(RB1):​c.1489A>G​(p.Thr497Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000025 in 1,596,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.37
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a region_of_interest Domain A (size 206) in uniprot entity RB_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000321.3
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RB1NM_000321.3 linkc.1489A>G p.Thr497Ala missense_variant Exon 16 of 27 ENST00000267163.6 NP_000312.2 P06400A0A024RDV3
RB1NM_001407165.1 linkc.1489A>G p.Thr497Ala missense_variant Exon 16 of 27 NP_001394094.1
RB1NM_001407166.1 linkc.1489A>G p.Thr497Ala missense_variant Exon 16 of 17 NP_001394095.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RB1ENST00000267163.6 linkc.1489A>G p.Thr497Ala missense_variant Exon 16 of 27 1 NM_000321.3 ENSP00000267163.4 P06400
RB1ENST00000650461.1 linkc.1489A>G p.Thr497Ala missense_variant Exon 16 of 27 ENSP00000497193.1 A0A3B3IS71

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151686
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000808
AC:
2
AN:
247442
Hom.:
0
AF XY:
0.00000747
AC XY:
1
AN XY:
133924
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000179
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000208
AC:
3
AN:
1445302
Hom.:
0
Cov.:
30
AF XY:
0.00000278
AC XY:
2
AN XY:
719766
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000273
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151686
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74016
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinoblastoma Uncertain:1
Aug 25, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine with alanine at codon 497 of the RB1 protein (p.Thr497Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs776531398, ExAC 0.002%) but has not been reported in the literature in individuals with a RB1-related disease. 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. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.78
D;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.81
T;T
M_CAP
Benign
0.044
D
MetaRNN
Uncertain
0.58
D;D
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Benign
1.1
L;.
PrimateAI
Benign
0.43
T
PROVEAN
Uncertain
-2.4
N;.
REVEL
Uncertain
0.62
Sift
Benign
0.48
T;.
Sift4G
Benign
0.061
T;.
Polyphen
0.78
P;.
Vest4
0.82
MutPred
0.69
Gain of catalytic residue at S501 (P = 0.0179);Gain of catalytic residue at S501 (P = 0.0179);
MVP
0.91
MPC
0.91
ClinPred
0.66
D
GERP RS
5.6
Varity_R
0.58
gMVP
0.57

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: rs776531398; hg19: chr13-48954368; API