rs759465865

Variant names:

• chr13-48303939-GGCCGCCACC-G
• rs759465865
• NM_000321.3:c.34_42delACCGCCGCC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000321.3(RB1):​c.34_42delACCGCCGCC​(p.Thr12_Ala14del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 1,357,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T12T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: RB1 NM_000321.3 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.97
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 13-48303939-GGCCGCCACC-G is Benign according to our data. Variant chr13-48303939-GGCCGCCACC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 410933.
• BS2: High AC in GnomAdExome4 at 25 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.34_42delACCGCCGCC	p.Thr12_Ala14del	conservative_inframe_deletion	Exon 1 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.34_42delACCGCCGCC	p.Thr12_Ala14del	conservative_inframe_deletion	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.34_42delACCGCCGCC	p.Thr12_Ala14del	conservative_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.34_42delACCGCCGCC	p.Thr12_Ala14del	conservative_inframe_deletion	Exon 1 of 27	ENSP00000267163.4	P06400
	RB1	ENST00000467505.6	TSL:1	n.34_42delACCGCCGCC		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
	RB1	ENST00000924352.1		c.34_42delACCGCCGCC	p.Thr12_Ala14del	conservative_inframe_deletion	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000761 AC: 8 AN: 105152 AF XY: 0.0000681

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000466

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000310

GnomAD4 exome AF: 0.0000184 AC: 25 AN: 1357732 Hom.: 0 AF XY: 0.0000164 AC XY: 11 AN XY: 669812

African (AFR) AF: 0.0000360 AC: 1 AN: 27786

American (AMR) AF: 0.0000301 AC: 1 AN: 33254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24212

East Asian (EAS) AF: 0.00 AC: 0 AN: 32404

South Asian (SAS) AF: 0.000183 AC: 14 AN: 76662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4008

European-Non Finnish (NFE) AF: 0.00000468 AC: 5 AN: 1068608

Other (OTH) AF: 0.0000707 AC: 4 AN: 56566

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.000290 AC: 1 AN: 3458

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Retinoblastoma (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=193/7	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs759465865; hg19: chr13-48878075;