rs183898408

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000321.3(RB1):​c.920C>G​(p.Thr307Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. T307I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

RB1
NM_000321.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.94
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.17462966).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RB1NM_000321.3 linkuse as main transcriptc.920C>G p.Thr307Arg missense_variant 9/27 ENST00000267163.6
LOC112268118XR_002957522.2 linkuse as main transcriptn.146G>C non_coding_transcript_exon_variant 3/3
RB1NM_001407165.1 linkuse as main transcriptc.920C>G p.Thr307Arg missense_variant 9/27
RB1NM_001407166.1 linkuse as main transcriptc.920C>G p.Thr307Arg missense_variant 9/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RB1ENST00000267163.6 linkuse as main transcriptc.920C>G p.Thr307Arg missense_variant 9/271 NM_000321.3 P1
RB1ENST00000650461.1 linkuse as main transcriptc.920C>G p.Thr307Arg missense_variant 9/27

Frequencies

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

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 21, 2020The p.T307R variant (also known as c.920C>G), located in coding exon 9 of the RB1 gene, results from a C to G substitution at nucleotide position 920. The threonine at codon 307 is replaced by arginine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.013
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
18
DANN
Benign
0.92
DEOGEN2
Benign
0.27
T;.
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.032
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.50
T
MutationAssessor
Benign
-0.34
N;.
MutationTaster
Benign
0.64
N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.57
N;.
REVEL
Benign
0.28
Sift
Benign
0.51
T;.
Sift4G
Benign
0.39
T;.
Polyphen
0.0
B;.
Vest4
0.40
MutPred
0.41
Gain of catalytic residue at S302 (P = 0.0014);Gain of catalytic residue at S302 (P = 0.0014);
MVP
0.60
MPC
0.67
ClinPred
0.44
T
GERP RS
5.6
Varity_R
0.27
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: chr13-48939088; API