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GeneBe

13-48456349-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000321.3(RB1):c.1960G>T(p.Val654Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in Lovd as Likely pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V654A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RB1
NM_000321.3 missense, splice_region

Scores

3
10
6
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.92
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 Pathogenic. Variant got 11 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a region_of_interest Domain B (size 131) in uniprot entity RB_HUMAN there are 40 pathogenic changes around while only 13 benign (75%) in NM_000321.3
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr13-48456349-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 100808.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 13-48456349-G-T is Pathogenic according to our data. Variant chr13-48456349-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RB1NM_000321.3 linkuse as main transcriptc.1960G>T p.Val654Leu missense_variant, splice_region_variant 19/27 ENST00000267163.6
RB1NM_001407165.1 linkuse as main transcriptc.1960G>T p.Val654Leu missense_variant, splice_region_variant 19/27

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RB1ENST00000267163.6 linkuse as main transcriptc.1960G>T p.Val654Leu missense_variant, splice_region_variant 19/271 NM_000321.3 P1
RB1ENST00000650461.1 linkuse as main transcriptc.1960G>T p.Val654Leu missense_variant, splice_region_variant 19/27
RB1ENST00000643064.1 linkuse as main transcriptc.194+74906G>T intron_variant
RB1ENST00000480491.1 linkuse as main transcript downstream_gene_variant 5

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
Cadd
Uncertain
25
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.68
D;.
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.042
D
MetaRNN
Uncertain
0.66
D;D
MetaSVM
Uncertain
0.18
D
MutationAssessor
Benign
0.55
N;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-1.3
N;.
REVEL
Uncertain
0.48
Sift
Benign
0.28
T;.
Sift4G
Benign
0.97
T;.
Polyphen
0.35
B;.
Vest4
0.44
MutPred
0.78
Gain of catalytic residue at Y659 (P = 0.0117);Gain of catalytic residue at Y659 (P = 0.0117);
MVP
0.97
MPC
1.3
ClinPred
0.86
D
GERP RS
6.0
Varity_R
0.58
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.22
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.22
Position offset: 0

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: chr13-49030485; COSMIC: COSV57322012; COSMIC: COSV57322012; API