13-48364952-C-T

Variant names:

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

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]

RB1 links:

LOC112268118 (HGNC:):

LOC112268118 links:

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
RB1	NM_000321.3 link	c.920C>T	p.Thr307Ile	missense_variant	Exon 9 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.920C>T	p.Thr307Ile	missense_variant	Exon 9 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.920C>T	p.Thr307Ile	missense_variant	Exon 9 of 17		NP_001394095.1
LOC112268118	XR_002957522.2 link	n.146G>A		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.920C>T	p.Thr307Ile	missense_variant	Exon 9 of 27	1	NM_000321.3	ENSP00000267163.4		P06400
RB1	ENST00000650461.1 link	c.920C>T	p.Thr307Ile	missense_variant	Exon 9 of 27			ENSP00000497193.1		A0A3B3IS71

Frequencies

GnomAD3 genomes

AF:

0.000869

AC:

132

AN:

151964

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

AF XY:

0.00110

AC XY:

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.:

Bravo

AF:

0.000861

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000467

AC:

ESP6500EA

AF:

0.000943

AC:

ExAC

AF:

0.000951

AC:

112

Asia WGS

AF:

0.00231

AC:

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

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2020	The 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 11, 2022	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 11, 2019	Variant 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Retinoblastoma

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 12, 2018	This 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 submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2025	RB1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2018	This 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 submitter	clinical testing	Ambry Genetics	Apr 11, 2019	This 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 submitter	curation	Sema4, Sema4	Oct 08, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.55

N;.

PrimateAI

Benign

0.42

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over