13-48362957-G-T

Variant summary

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

The NM_000321.3(RB1):​c.861G>T​(p.Glu287Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

RB1
NM_000321.3 missense, splice_region

Scores

7
9
3
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.83
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
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RB1NM_000321.3 linkc.861G>T p.Glu287Asp missense_variant, splice_region_variant Exon 8 of 27 ENST00000267163.6 NP_000312.2 P06400A0A024RDV3
RB1NM_001407165.1 linkc.861G>T p.Glu287Asp missense_variant, splice_region_variant Exon 8 of 27 NP_001394094.1
RB1NM_001407166.1 linkc.861G>T p.Glu287Asp missense_variant, splice_region_variant Exon 8 of 17 NP_001394095.1
LOC112268118XR_002957522.2 linkn.*231C>A downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RB1ENST00000267163.6 linkc.861G>T p.Glu287Asp missense_variant, splice_region_variant Exon 8 of 27 1 NM_000321.3 ENSP00000267163.4 P06400
RB1ENST00000650461.1 linkc.861G>T p.Glu287Asp missense_variant, splice_region_variant Exon 8 of 27 ENSP00000497193.1 A0A3B3IS71
RB1ENST00000467505.5 linkn.*229G>T downstream_gene_variant 1 ENSP00000434702.1 Q92728

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.61
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.53
D;.
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.78
T;T
M_CAP
Uncertain
0.28
D
MetaRNN
Uncertain
0.60
D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.8
N;.
REVEL
Uncertain
0.63
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.70
MutPred
0.50
Loss of methylation at K289 (P = 0.0647);Loss of methylation at K289 (P = 0.0647);
MVP
0.93
MPC
0.66
ClinPred
0.97
D
GERP RS
5.2
Varity_R
0.74
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.72
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.62
Position offset: 48
DS_DL_spliceai
0.72
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: chr13-48937093; API