rs3092904

Positions:

• chr13-48477345-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000321.3(RB1):​c.2664-10T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,598,702 control chromosomes in the GnomAD database, including 49,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3473 hom., cov: 33)
  • Exomes 𝑓: 0.25 (46321 hom.)
• Consequence: RB1 NM_000321.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0005315
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.676

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 13-48477345-T-A is Benign according to our data. Variant chr13-48477345-T-A is described in ClinVar as [Benign]. Clinvar id is 92843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48477345-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.2664-10T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000267163.6
RB1	NM_001407165.1	c.2664-10T>A		splice_polypyrimidine_tract_variant, intron_variant
RB1	NM_001407168.1	c.114-10T>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.2664-10T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000321.3	P1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30705 AN: 152034 Hom.: 3477 Cov.: 33

Gnomad AFR AF: 0.0960

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.194

GnomAD3 exomes AF: 0.237 AC: 58755 AN: 247544 Hom.: 7381 AF XY: 0.241 AC XY: 32195 AN XY: 133798

Gnomad AFR exome AF: 0.0925

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.239

Gnomad SAS exome AF: 0.272

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.235

GnomAD4 exome AF: 0.249 AC: 360651 AN: 1446550 Hom.: 46321 Cov.: 30 AF XY: 0.250 AC XY: 179672 AN XY: 720096

Gnomad4 AFR exome AF: 0.0871

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.242

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.268

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.237

GnomAD4 genome AF: 0.202 AC: 30698 AN: 152152 Hom.: 3473 Cov.: 33 AF XY: 0.205 AC XY: 15222 AN XY: 74362

Gnomad4 AFR AF: 0.0957

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.229

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.267

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.191

Alfa AF: 0.225 Hom.: 735

Bravo AF: 0.192

Asia WGS AF: 0.233 AC: 806 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 12, 2022	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 25, 2016

Variant summary: The RB1 c.2664-10T>A variant involves the alteration of a non-conserved intronic nucleotide with 4/5 splice prediction tools predict no significant impact on splicing and the creation of a ESE binding site, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 28338/108858 (3633 homozygotes, 1/3, frequency: 0.2603208), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic RB1 variant of 1/23980 (0.0000417), suggesting this variant is likely a benign polymorphism. In addition, a reputable clinical laboratory cites the variant as "benign." Taken together and based on the high allele frequency in the general population, the variant of interest is classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.015
DANN	Benign	0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
dbscSNV1_RF	Benign	0.062
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

Other links and lift over

dbSNP: rs3092904; hg19: chr13-49051481; COSMIC: COSV57294376;