chr13-48477345-T-A

Position:

chr13-48477345-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000267163.6(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
ENST00000267163.6 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0005315

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.676

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Effect	MANE	Protein
RB1	NM_000321.3 linkuse as main transcript	c.2664-10T>A	splice_polypyrimidine_tract_variant, intron_variant	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1 linkuse as main transcript	c.2664-10T>A	splice_polypyrimidine_tract_variant, intron_variant		NP_001394094.1
RB1	NM_001407168.1 linkuse as main transcript	c.114-10T>A	splice_polypyrimidine_tract_variant, intron_variant		NP_001394097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 linkuse as main transcript	c.2664-10T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000321.3	ENSP00000267163	P1

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30705

AN:

152034

Hom.:

3477

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.250

AC XY:

179672

AN XY:

720096

show subpopulations

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.:

AF XY:

0.205

AC XY:

15222

AN XY:

74362

show subpopulations

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Benign:6

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 03, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 12, 2022	- -
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	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	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. -
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	-	- -

not provided

Benign:2

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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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