chr13-48380042-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

hereditary retinoblastoma
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
retinoblastoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
melanoma
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

RB1 links:

LOC112268118 (HGNC:):

LOC112268118 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 255821.

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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 481 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.1390-11A>G	intron_variant	Intron 14 of 26	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.1390-11A>G	intron_variant	Intron 14 of 26		NP_001394094.1
RB1	NM_001407166.1 link	c.1390-11A>G	intron_variant	Intron 14 of 16		NP_001394095.1
LOC112268118	XR_002957522.2 link	n.-168T>C	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.1390-11A>G		intron_variant	Intron 14 of 26	1	NM_000321.3	ENSP00000267163.4		P06400

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

GnomAD2 exomes

AF:

0.000596

AC:

AN:

114180

AF XY:

0.000530

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 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

African (AFR)

AF:

0.0107

AC:

228

AN:

21274

American (AMR)

AF:

0.000793

AC:

AN:

18918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17648

East Asian (EAS)

AF:

0.00

AC:

AN:

24758

South Asian (SAS)

AF:

0.0000335

AC:

AN:

59688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37000

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

2870

European-Non Finnish (NFE)

AF:

0.0000265

AC:

AN:

830796

Other (OTH)

AF:

0.00127

AC:

AN:

41838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00336

AC:

481

AN:

143254

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

221

AN XY:

69490

show subpopulations

African (AFR)

AF:

0.0120

AC:

466

AN:

38948

American (AMR)

AF:

0.000353

AC:

AN:

14148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3378

East Asian (EAS)

AF:

0.00

AC:

AN:

4940

South Asian (SAS)

AF:

0.00

AC:

AN:

4532

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000910

AC:

AN:

65920

Other (OTH)

AF:

0.00202

AC:

AN:

1978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00274

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

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely 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 28, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 04, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RB1: BS1 -

Hereditary cancer-predisposing syndrome

Uncertain:1

Oct 21, 2014

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over