13-48303948-CGCCGCCGCT-C

Position:

• chr13-48303948-CGCCGCCGCT-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (25 hom.)
• Consequence: RB1 NM_000321.3 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 1.49

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 13-48303948-CGCCGCCGCT-C is Benign according to our data. Variant chr13-48303948-CGCCGCCGCT-C is described in ClinVar 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 Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1631 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	1/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	1/27		NP_001394094.1
RB1	NM_001407166.1	c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	1/17		NP_001394095.1
RB1	NM_001407167.1	c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	1/3		NP_001394096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	1/27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1623 AN: 152016 Hom.: 27 Cov.: 32

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

GnomAD3 exomes AF: 0.00105 AC: 110 AN: 105080 Hom.: 3 AF XY: 0.000801 AC XY: 47 AN XY: 58652

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 SAS exome AF: 0.000252

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.: 25 AF XY: 0.000872 AC XY: 584 AN XY: 669568

Gnomad4 AFR exome AF: 0.0388

Gnomad4 AMR exome AF: 0.00202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000402

Gnomad4 OTH exome AF: 0.00264

GnomAD4 genome AF: 0.0107 AC: 1631 AN: 152124 Hom.: 28 Cov.: 32 AF XY: 0.0106 AC XY: 789 AN XY: 74390

Gnomad4 AFR AF: 0.0372

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00614 Hom.: 5

Bravo AF: 0.0120

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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: African  in 60 of 1 794 chromosomes (freq: 0.0334), European (Non-Finnish)  in 3 of 38 746 chromosomes (freq: 0.000077), Latino  in 41 of 21 494 chromosomes (freq: 0.00191), South Asian  in 5 of 19 876 chromosomes (freq: 0.000252), and Other  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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2016	This variant is associated with the following publications: (PMID: 24728327) -

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 21, 2022	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. -

Retinoblastoma Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 02, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2017

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs572454921; hg19: chr13-48878084;