chr13-48380042-A-G

Position:

chr13-48380042-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000321.3(RB1):c.1390-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 1,198,044 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 7 hom., cov: 30)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

RB1
NM_000321.3 intron

Scores

Splicing: ADA: 0.00007313

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.05

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 13-48380042-A-G is Benign according to our data. Variant chr13-48380042-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255821.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=5}. Variant chr13-48380042-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00336 (481/143254) while in subpopulation AFR AF= 0.012 (466/38948). AF 95% confidence interval is 0.0111. There are 7 homozygotes in gnomad4. There are 221 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 481 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
RB1	NM_000321.3 linkuse as main transcript	c.1390-11A>G	intron_variant	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 linkuse as main transcript	c.1390-11A>G	intron_variant		NP_001394094.1
RB1	NM_001407166.1 linkuse as main transcript	c.1390-11A>G	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.1390-11A>G		intron_variant		1	NM_000321.3	ENSP00000267163.4		P06400
RB1	ENST00000650461.1 linkuse as main transcript	c.1390-11A>G		intron_variant				ENSP00000497193.1		A0A3B3IS71

Frequencies

GnomAD3 genomes

AF:

0.00337

AC:

483

AN:

143206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000354

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000220

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000910

Gnomad OTH

AF:

0.00204

GnomAD3 exomes

AF:

0.000596

AC:

AN:

114180

Hom.:

AF XY:

0.000530

AC XY:

AN XY:

64186

show subpopulations

Gnomad AFR exome

AF:

0.00833

Gnomad AMR exome

AF:

0.000481

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000605

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000837

Gnomad OTH exome

AF:

0.00142

GnomAD4 exome

AF:

0.000306

AC:

323

AN:

1054790

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

135

AN XY:

526366

show subpopulations

Gnomad4 AFR exome

AF:

0.0107

Gnomad4 AMR exome

AF:

0.000793

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000335

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000265

Gnomad4 OTH exome

AF:

0.00127

GnomAD4 genome

AF:

0.00336

AC:

481

AN:

143254

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

221

AN XY:

69490

show subpopulations

Gnomad4 AFR

AF:

0.0120

Gnomad4 AMR

AF:

0.000353

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000910

Gnomad4 OTH

AF:

0.00202

Alfa

AF:

0.00144

Hom.:

Bravo

AF:

0.00379

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinoblastoma

Benign:4

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	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 28, 2022	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RB1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2014

The c.1390-11A>G intronic variant results from an A to G substitution 11 nucleotides upstream from coding exon 15 in the RB1 gene. This variant was previously reported in the SNPDatabase as rs200658795. Based on data from the 1000 Genomes Project, the G allele has an overall frequency of approximately 0.1% (2/2,098) total alleles studied. The highest observed frequency was 0.57% (1/176) Yoruba alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.22% (23/10,564) total alleles studied, having been observed in 0.7% (23/3,288) African American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.29% (greater than 350 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration does not have any significant effect on this splice donor site (http://www.fruitfly.org/seq_tools/splice.html and http://rulai.cshl.edu/cgi-bin/tools/ESE3/esefinder.cgi). However, experimental evidence is not available. Since supporting evidence is limited at this time, the clinical significance of c.1390-11A>G remains unclear. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000073

dbscSNV1_RF

Benign

0.084

SpliceAI score (max)

0.010

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