13-48453060-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_000321.3(RB1):​c.1763C>T​(p.Ser588Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,460,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S588S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.72
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_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.25018004).
BS2
High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RB1NM_000321.3 linkuse as main transcriptc.1763C>T p.Ser588Phe missense_variant 18/27 ENST00000267163.6
RB1NM_001407165.1 linkuse as main transcriptc.1763C>T p.Ser588Phe missense_variant 18/27

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RB1ENST00000267163.6 linkuse as main transcriptc.1763C>T p.Ser588Phe missense_variant 18/271 NM_000321.3 P1
RB1ENST00000650461.1 linkuse as main transcriptc.1763C>T p.Ser588Phe missense_variant 18/27
RB1ENST00000643064.1 linkuse as main transcriptc.194+71617C>T intron_variant
RB1ENST00000480491.1 linkuse as main transcriptn.462C>T non_coding_transcript_exon_variant 2/35

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1460982
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
726818
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:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinoblastoma Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthNov 30, 2023This missense variant replaces serine with phenylalanine at codon 588 of the RB1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RB1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 24, 2024This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 588 of the RB1 protein (p.Ser588Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 458136). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 21, 2022The p.S588F variant (also known as c.1763C>T), located in coding exon 18 of the RB1 gene, results from a C to T substitution at nucleotide position 1763. The serine at codon 588 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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
0.13
BayesDel_addAF
Uncertain
0.085
D
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.47
T;.
Eigen
Benign
0.063
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.036
D
MetaRNN
Benign
0.25
T;T
MetaSVM
Uncertain
-0.042
T
MutationAssessor
Benign
0.0
N;.
MutationTaster
Benign
0.86
N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.84
N;.
REVEL
Uncertain
0.37
Sift
Benign
0.031
D;.
Sift4G
Uncertain
0.010
D;.
Polyphen
0.25
B;.
Vest4
0.30
MutPred
0.44
Gain of catalytic residue at E587 (P = 6e-04);Gain of catalytic residue at E587 (P = 6e-04);
MVP
0.83
MPC
0.63
ClinPred
0.61
D
GERP RS
5.8
Varity_R
0.29
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1555293637; hg19: chr13-49027196; COSMIC: COSV57321183; API