NM_000321.3:c.45_53delTGCCGCCGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000321.3(RB1):c.45_53delTGCCGCCGC(p.Ala16_Ala18del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,509,402 control chromosomes in the GnomAD database, including 53 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A15A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 28 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 25 hom. )

Consequence

RB1
NM_000321.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 1.49

Publications

3 publications found

Variant links:

COSMIC-nc: COSV57297386

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:

RB1-DT (HGNC:42778): (RB1 divergent transcript)

RB1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 13-48303948-CGCCGCCGCT-C is Benign according to our data. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48303948-CGCCGCCGCT-C is described in CliVar as Benign. Clinvar id is 193082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1631/152124) while in subpopulation AFR AF = 0.0372 (1544/41506). AF 95% confidence interval is 0.0357. There are 28 homozygotes in GnomAd4. There are 789 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1631 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	Exon 1 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	Exon 1 of 27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1623

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0371

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00105

AC:

110

AN:

105080

AF XY:

0.000801

show subpopulations

Gnomad AFR exome

AF:

0.0334

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000774

Gnomad OTH exome

AF:

0.000310

GnomAD4 exome

AF:

0.000995

AC:

1351

AN:

1357278

Hom.:

AF XY:

0.000872

AC XY:

584

AN XY:

669568

show subpopulations

African (AFR)

AF:

0.0388

AC:

1078

AN:

27772

American (AMR)

AF:

0.00202

AC:

AN:

33220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24184

East Asian (EAS)

AF:

0.00

AC:

AN:

32406

South Asian (SAS)

AF:

0.000118

AC:

AN:

76574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34092

Middle Eastern (MID)

AF:

0.00124

AC:

AN:

4026

European-Non Finnish (NFE)

AF:

0.0000402

AC:

AN:

1068464

Other (OTH)

AF:

0.00264

AC:

149

AN:

56540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

146

218

291

364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.0107

AC:

1631

AN:

152124

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

789

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0372

AC:

1544

AN:

41506

American (AMR)

AF:

0.00471

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67958

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

140

209

279

349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00614

Hom.:

Bravo

AF:

0.0120

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RB1 p.Ala16_Ala18del variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs572454921) and in ClinVar (classified as Benign by Invitae, Ambry Genetics and EGL Genetic Diagnostics. Conditions associated as Retinoblastoma and Hereditary cancer-predisposing syndrome). The variant was identified in control databases in 110 of 105 080 chromosomes (3 homozygous) at a frequency of 0.001047 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: AfricanÂ¬â€ in 60 of 1 794 chromosomes (freq: 0.0334), European (Non-Finnish)Â¬â€ in 3 of 38 746 chromosomes (freq: 0.000077), LatinoÂ¬â€ in 41 of 21 494 chromosomes (freq: 0.00191), South AsianÂ¬â€ in 5 of 19 876 chromosomes (freq: 0.000252), and OtherÂ¬â€ in 1 of 3 226 chromosomes (freq: 0.000309); it was not observed in the Ashkenazi Jewish, East Asian and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. This variant is an in-frame deletion resulting in the removal of Ala residues between codons 16-18; the impact of this alteration on RB1 protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Jul 14, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24728327) -

Sep 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2Other:1

Aug 25, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RB1 c.45_53delTGCCGCCGC (p.Ala16_Ala18del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant allele was found at a frequency of 0.001 in 105080 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 25 fold of the estimated maximal predicted allele frequency for a pathogenic variant in RB1 causing Retinoblastoma phenotype (4.2e-05), strongly suggesting that the variant is benign. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Retinoblastoma

Benign:2

Feb 02, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Nov 30, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

RB1-related disorder

Benign:1

Oct 24, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Mutation Taster

=199/1

polymorphism

(source)

Splicing

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