rs572454921

Variant names:

• chr13-48303948-CGCCGCCGCT-C
• rs572454921
• NM_000321.3:c.45_53delTGCCGCCGC

Your query was ambiguous. Multiple possible variants found:

• chr13-48303948-CGCCGCCGCT-C
• chr13-48303948-CGCCGCCGCT-CGCCGCCGCTGCCGCCGCT

Variant summary

Our verdict is Benign. The variant received -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 (★★). 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 1.49
• Publications: 3 publications found

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

ACMG classification

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 ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	Exon 1 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	Exon 1 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.45_53delTGCCGCCGC		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.45_53delTGCCGCCGC	p.Ala16_Ala18del	disruptive_inframe_deletion	Exon 1 of 28	ENSP00000594411.1

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

GnomAD2 exomes AF: 0.00105 AC: 110 AN: 105080 AF XY: 0.000801

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

African (AFR) AF: 0.0388 AC: 1078 AN: 27772

American (AMR) AF: 0.00202 AC: 67 AN: 33220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24184

East Asian (EAS) AF: 0.00 AC: 0 AN: 32406

South Asian (SAS) AF: 0.000118 AC: 9 AN: 76574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34092

Middle Eastern (MID) AF: 0.00124 AC: 5 AN: 4026

European-Non Finnish (NFE) AF: 0.0000402 AC: 43 AN: 1068464

Other (OTH) AF: 0.00264 AC: 149 AN: 56540

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

African (AFR) AF: 0.0372 AC: 1544 AN: 41506

American (AMR) AF: 0.00471 AC: 72 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67958

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00614 Hom.: 5

Bravo AF: 0.0120

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (3)
-	-	2	Retinoblastoma (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	RB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=199/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs572454921; hg19: chr13-48878084; COSMIC: COSV57297386;