Genetic Variant NM_000321.3:c.78_83dupGCCCCC (chr13-48303987-G-GCCGCCC) – 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.78_83dupGCCCCC(p.Pro27_Pro28dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,346,554 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. P28P) 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:2

Conservation

PhyloP100: 0.858

Publications

0 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 Gene-Disease associations (from GenCC):

hereditary retinoblastoma
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
retinoblastoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
melanoma
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

RB1 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.78_83dupGCCCCC	p.Pro27_Pro28dup	disruptive_inframe_insertion	Exon 1 of 27	NP_000312.2	P06400
RB1	NM_001407165.1		c.78_83dupGCCCCC	p.Pro27_Pro28dup	disruptive_inframe_insertion	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
RB1	NM_001407166.1		c.78_83dupGCCCCC	p.Pro27_Pro28dup	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.78_83dupGCCCCC	p.Pro27_Pro28dup	disruptive_inframe_insertion	Exon 1 of 27	ENSP00000267163.4	P06400
RB1	ENST00000467505.6	TSL:1	n.78_83dupGCCCCC		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
RB1	ENST00000924352.1		c.78_83dupGCCCCC	p.Pro27_Pro28dup	disruptive_inframe_insertion	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.43e-7

AC:

AN:

1346554

Hom.:

Cov.:

AF XY:

0.00000151

AC XY:

AN XY:

664122

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:

27212

American (AMR)

AF:

0.0000325

AC:

AN:

30782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23728

East Asian (EAS)

AF:

0.00

AC:

AN:

31572

South Asian (SAS)

AF:

0.00

AC:

AN:

75594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4034

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1064042

Other (OTH)

AF:

0.00

AC:

AN:

56006

⚠️ 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: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

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)

Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.86

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