13-48380039-A-T

Position:

chr13-48380039-A-T

Variant summary

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

The NM_000321.3(RB1):c.1390-14A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 1,242,656 control chromosomes in the GnomAD database, including 2,392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 221 hom., cov: 29)

Exomes 𝑓: 0.056 ( 2171 hom. )

Consequence

RB1
NM_000321.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.649

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=-0.82).

BP6

Variant 13-48380039-A-T is Benign according to our data. Variant chr13-48380039-A-T is described in ClinVar as [Benign]. Clinvar id is 167566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
RB1	NM_000321.3 linkuse as main transcript	c.1390-14A>T	intron_variant	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 linkuse as main transcript	c.1390-14A>T	intron_variant		NP_001394094.1
RB1	NM_001407166.1 linkuse as main transcript	c.1390-14A>T	intron_variant		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 linkuse as main transcript	c.1390-14A>T		intron_variant		1	NM_000321.3	ENSP00000267163.4		P06400
RB1	ENST00000650461.1 linkuse as main transcript	c.1390-14A>T		intron_variant				ENSP00000497193.1		A0A3B3IS71

Frequencies

GnomAD3 genomes

AF:

0.0471

AC:

6973

AN:

148040

Hom.:

221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.0927

Gnomad AMR

AF:

0.0458

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.000588

Gnomad SAS

AF:

0.00909

Gnomad FIN

AF:

0.0448

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0753

Gnomad OTH

AF:

0.0541

GnomAD3 exomes

AF:

0.0417

AC:

4720

AN:

113174

Hom.:

154

AF XY:

0.0410

AC XY:

2607

AN XY:

63566

show subpopulations

Gnomad AFR exome

AF:

0.00792

Gnomad AMR exome

AF:

0.0260

Gnomad ASJ exome

AF:

0.0322

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0127

Gnomad FIN exome

AF:

0.0573

Gnomad NFE exome

AF:

0.0640

Gnomad OTH exome

AF:

0.0426

GnomAD4 exome

AF:

0.0556

AC:

60894

AN:

1094532

Hom.:

2171

Cov.:

AF XY:

0.0549

AC XY:

30092

AN XY:

547818

show subpopulations

Gnomad4 AFR exome

AF:

0.00764

Gnomad4 AMR exome

AF:

0.0306

Gnomad4 ASJ exome

AF:

0.0351

Gnomad4 EAS exome

AF:

0.0000683

Gnomad4 SAS exome

AF:

0.0106

Gnomad4 FIN exome

AF:

0.0529

Gnomad4 NFE exome

AF:

0.0639

Gnomad4 OTH exome

AF:

0.0483

GnomAD4 genome

AF:

0.0470

AC:

6969

AN:

148124

Hom.:

221

Cov.:

AF XY:

0.0449

AC XY:

3238

AN XY:

72146

show subpopulations

Gnomad4 AFR

AF:

0.0120

Gnomad4 AMR

AF:

0.0457

Gnomad4 ASJ

AF:

0.0305

Gnomad4 EAS

AF:

0.000589

Gnomad4 SAS

AF:

0.00869

Gnomad4 FIN

AF:

0.0448

Gnomad4 NFE

AF:

0.0753

Gnomad4 OTH

AF:

0.0536

Alfa

AF:

0.0568

Hom.:

Bravo

AF:

0.0471

Asia WGS

AF:

0.0240

AC:

AN:

3464

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Benign:5

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 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Color Diagnostics, LLC DBA Color Health	Apr 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 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:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: The RB1 c.1390-14A>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 1084/24708 control chromosomes (28 homozygotes) at a frequency of 0.0438724, which is approximately 1053 times the estimated maximal expected allele frequency of a pathogenic RB1 variant (0.0000417), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Dec 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.2

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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