Genetic Variant NM_000321.3:c.45_53dupTGCCGCCGC (chr13-48303948-C-CGCCGCCGCT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000321.3(RB1):c.45_53dupTGCCGCCGC(p.Ala16_Ala18dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,357,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A18A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

RB1
NM_000321.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.0430

Publications

3 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 links:

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

RB1-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RB1	NM_000321.3	MANE Select	c.45_53dupTGCCGCCGC	p.Ala16_Ala18dup	disruptive_inframe_insertion	Exon 1 of 27	NP_000312.2	P06400
RB1	NM_001407165.1		c.45_53dupTGCCGCCGC	p.Ala16_Ala18dup	disruptive_inframe_insertion	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
RB1	NM_001407166.1		c.45_53dupTGCCGCCGC	p.Ala16_Ala18dup	disruptive_inframe_insertion	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RB1	ENST00000267163.6	TSL:1 MANE Select	c.45_53dupTGCCGCCGC	p.Ala16_Ala18dup	disruptive_inframe_insertion	Exon 1 of 27	ENSP00000267163.4	P06400
RB1	ENST00000467505.6	TSL:1	n.45_53dupTGCCGCCGC		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
RB1	ENST00000924352.1		c.45_53dupTGCCGCCGC	p.Ala16_Ala18dup	disruptive_inframe_insertion	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.37e-7

AC:

AN:

1357280

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

669570

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27772

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

76574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4026

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1068464

Other (OTH)

AF:

0.00

AC:

AN:

56542

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Malignant tumor of urinary bladder;C0035335:Retinoblastoma;C0149925:Small cell lung carcinoma;C0585442:Bone osteosarcoma (1)

Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.043

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over