rs1555293654

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000321.3(RB1):​c.1814T>A​(p.Met605Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on 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

2
11
6
Splicing: ADA: 0.8285
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.98
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 Uncertain_significance. Variant got 2 ACMG points.

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.1814T>A p.Met605Lys missense_variant, splice_region_variant Exon 18 of 27 ENST00000267163.6 NP_000312.2 P06400A0A024RDV3
RB1NM_001407165.1 linkc.1814T>A p.Met605Lys missense_variant, splice_region_variant Exon 18 of 27 NP_001394094.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RB1ENST00000267163.6 linkc.1814T>A p.Met605Lys missense_variant, splice_region_variant Exon 18 of 27 1 NM_000321.3 ENSP00000267163.4 P06400
RB1ENST00000650461.1 linkc.1814T>A p.Met605Lys missense_variant, splice_region_variant Exon 18 of 27 ENSP00000497193.1 A0A3B3IS71
RB1ENST00000643064.1 linkc.192+71668T>A intron_variant Intron 1 of 1 ENSP00000496005.1 A0A2R8Y743
RB1ENST00000480491.1 linkn.513T>A splice_region_variant, non_coding_transcript_exon_variant Exon 2 of 3 5

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
0.84
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
CADD
Uncertain
24
DANN
Benign
0.97
DEOGEN2
Benign
0.41
T;.
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Uncertain
0.086
D
MetaRNN
Uncertain
0.46
T;T
MetaSVM
Uncertain
0.26
D
MutationAssessor
Benign
1.4
L;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.4
N;.
REVEL
Uncertain
0.56
Sift
Benign
0.12
T;.
Sift4G
Uncertain
0.0020
D;.
Polyphen
0.72
P;.
Vest4
0.54
MutPred
0.39
Gain of ubiquitination at M605 (P = 0.0351);Gain of ubiquitination at M605 (P = 0.0351);
MVP
0.88
MPC
0.78
ClinPred
0.83
D
GERP RS
5.8
Varity_R
0.81
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.83
dbscSNV1_RF
Benign
0.66
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-49027247; API