13-48364952-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000321.3(RB1):​c.920C>T​(p.Thr307Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,571,430 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 7 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

6
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12O: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010866463).
BP6
Variant 13-48364952-C-T is Benign according to our data. Variant chr13-48364952-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135125.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=9, Likely_benign=3, not_provided=1}. Variant chr13-48364952-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000868 (132/152082) while in subpopulation SAS AF= 0.00374 (18/4810). AF 95% confidence interval is 0.00242. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 132 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RB1NM_000321.3 linkc.920C>T p.Thr307Ile missense_variant Exon 9 of 27 ENST00000267163.6 NP_000312.2 P06400A0A024RDV3
RB1NM_001407165.1 linkc.920C>T p.Thr307Ile missense_variant Exon 9 of 27 NP_001394094.1
RB1NM_001407166.1 linkc.920C>T p.Thr307Ile missense_variant Exon 9 of 17 NP_001394095.1
LOC112268118XR_002957522.2 linkn.146G>A non_coding_transcript_exon_variant Exon 3 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RB1ENST00000267163.6 linkc.920C>T p.Thr307Ile missense_variant Exon 9 of 27 1 NM_000321.3 ENSP00000267163.4 P06400
RB1ENST00000650461.1 linkc.920C>T p.Thr307Ile missense_variant Exon 9 of 27 ENSP00000497193.1 A0A3B3IS71

Frequencies

GnomAD3 genomes
AF:
0.000869
AC:
132
AN:
151964
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00295
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00374
Gnomad FIN
AF:
0.000379
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000853
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00131
AC:
260
AN:
197864
Hom.:
0
AF XY:
0.00164
AC XY:
174
AN XY:
106364
show subpopulations
Gnomad AFR exome
AF:
0.0000894
Gnomad AMR exome
AF:
0.00117
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00449
Gnomad FIN exome
AF:
0.000362
Gnomad NFE exome
AF:
0.00118
Gnomad OTH exome
AF:
0.000586
GnomAD4 exome
AF:
0.00113
AC:
1607
AN:
1419348
Hom.:
7
Cov.:
30
AF XY:
0.00129
AC XY:
907
AN XY:
702842
show subpopulations
Gnomad4 AFR exome
AF:
0.0000938
Gnomad4 AMR exome
AF:
0.00107
Gnomad4 ASJ exome
AF:
0.0000790
Gnomad4 EAS exome
AF:
0.0000266
Gnomad4 SAS exome
AF:
0.00462
Gnomad4 FIN exome
AF:
0.000395
Gnomad4 NFE exome
AF:
0.00103
Gnomad4 OTH exome
AF:
0.000583
GnomAD4 genome
AF:
0.000868
AC:
132
AN:
152082
Hom.:
0
Cov.:
32
AF XY:
0.00110
AC XY:
82
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00294
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00374
Gnomad4 FIN
AF:
0.000379
Gnomad4 NFE
AF:
0.000853
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00112
Hom.:
0
Bravo
AF:
0.000861
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000467
AC:
2
ESP6500EA
AF:
0.000943
AC:
8
ExAC
AF:
0.000951
AC:
112
Asia WGS
AF:
0.00231
AC:
8
AN:
3472

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:12Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:4Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalMar 04, 2025- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 11, 2019Variant summary: RB1 c.920C>T (p.Thr307Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 223688 control chromosomes, predominantly at a frequency of 0.0048 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 115 fold of the estimated maximal expected allele frequency for a pathogenic variant in RB1 causing Retinoblastoma phenotype (4.2e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.920C>T has been reported in the literature in individuals affected with Retinoblastoma (e.g. Brichard_2006, He_2014, Li_2016). Co-occurrences with other pathogenic variant(s) have been reported (RB1 c.871_872delGT), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJan 11, 2022- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 10, 2020The p.Thr307Ile variant in RB1 is classified as benign because it has been identified in 0.45% (117/26046) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -
Retinoblastoma Benign:4
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaSep 12, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 04, 2025- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2025RB1: BS1, BS2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 23, 2018This variant is associated with the following publications: (PMID: 28193182, 26107153, 20981092, 26332594, 26764160, 20090211, 24791139, 27181684, 27882345, 26396485, 17996702, 16343894, 25735316, 12541220, 24728327, 28780672, 33456302) -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 11, 2019This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submittercurationSema4, Sema4Oct 08, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Uncertain
0.040
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.42
T;.
Eigen
Benign
-0.11
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.84
T;T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.011
T;T
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Benign
0.55
N;.
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.6
N;.
REVEL
Uncertain
0.45
Sift
Benign
0.17
T;.
Sift4G
Benign
0.16
T;.
Polyphen
0.029
B;.
Vest4
0.72
MVP
0.93
MPC
0.55
ClinPred
0.0064
T
GERP RS
5.6
Varity_R
0.25
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs183898408; hg19: chr13-48939088; COSMIC: COSV57313105; COSMIC: COSV57313105; API