13-48364952-C-T

Variant names:

• chr13-48364952-C-T
• rs183898408
• NM_000321.3:c.920C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T307A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (7 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13 O:1
• Conservation: PhyloP100: 2.94

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]

LOC112268118 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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, not_provided=1, Likely_benign=3, Benign=10}. 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• 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	c.920C>T	p.Thr307Ile	missense_variant	Exon 9 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.920C>T	p.Thr307Ile	missense_variant	Exon 9 of 27		NP_001394094.1
RB1	NM_001407166.1	c.920C>T	p.Thr307Ile	missense_variant	Exon 9 of 17		NP_001394095.1
LOC112268118	XR_002957522.2	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	c.920C>T	p.Thr307Ile	missense_variant	Exon 9 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.920C>T	p.Thr307Ile	missense_variant	Exon 9 of 27			ENSP00000497193.1

Frequencies

GnomAD3 genomes AF: 0.000869 AC: 132 AN: 151964 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00131 AC: 260 AN: 197864 AF XY: 0.00164

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 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

Gnomad4 AFR exome AF: 0.0000938 AC: 3 AN: 31966

Gnomad4 AMR exome AF: 0.00107 AC: 45 AN: 42070

Gnomad4 ASJ exome AF: 0.0000790 AC: 2 AN: 25330

Gnomad4 EAS exome AF: 0.0000266 AC: 1 AN: 37622

Gnomad4 SAS exome AF: 0.00462 AC: 378 AN: 81792

Gnomad4 FIN exome AF: 0.000395 AC: 20 AN: 50620

Gnomad4 NFE exome AF: 0.00103 AC: 1115 AN: 1086192

Gnomad4 Remaining exome AF: 0.000583 AC: 34 AN: 58312

GnomAD4 genome AF: 0.000868 AC: 132 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74342

Gnomad4 AFR AF: 0.000121 AC: 0.000120552 AN: 0.000120552

Gnomad4 AMR AF: 0.00294 AC: 0.00294426 AN: 0.00294426

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000192976 AN: 0.000192976

Gnomad4 SAS AF: 0.00374 AC: 0.0037422 AN: 0.0037422

Gnomad4 FIN AF: 0.000379 AC: 0.000379075 AN: 0.000379075

Gnomad4 NFE AF: 0.000853 AC: 0.000853042 AN: 0.000853042

Gnomad4 OTH AF: 0.000473 AC: 0.000473485 AN: 0.000473485

Alfa AF: 0.00108 Hom.: 1

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:1 Benign:13 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:4 Other:1

Aug 10, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2022

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Apr 11, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Retinoblastoma Benign:5

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RB1: BS1, BS2 -

Jul 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 11, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 08, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		0.0
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

Other links and lift over

dbSNP: rs183898408; hg19: chr13-48939088; COSMIC: COSV57313105;