Genetic Variant NM_000321.3:c.78_80delGCC (chr13-48303978-ACCG-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000321.3(RB1):c.78_80delGCC(p.Pro27del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 1,348,762 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P26P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RB1
NM_000321.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.54

Publications

4 publications found

Variant links:

COSMIC-nc: COSV105078111

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 13-48303978-ACCG-A is Benign according to our data. Variant chr13-48303978-ACCG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 410949.

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_80delGCC	p.Pro27del	disruptive_inframe_deletion	Exon 1 of 27	NP_000312.2	P06400
RB1	NM_001407165.1		c.78_80delGCC	p.Pro27del	disruptive_inframe_deletion	Exon 1 of 27	NP_001394094.1	A0A3B3IS71
RB1	NM_001407166.1		c.78_80delGCC	p.Pro27del	disruptive_inframe_deletion	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_80delGCC	p.Pro27del	disruptive_inframe_deletion	Exon 1 of 27	ENSP00000267163.4	P06400
RB1	ENST00000467505.6	TSL:1	n.78_80delGCC		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1	Q92728
RB1	ENST00000924352.1		c.78_80delGCC	p.Pro27del	disruptive_inframe_deletion	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151892

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000340

AC:

AN:

97150

AF XY:

0.000293

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000613

Gnomad ASJ exome

AF:

0.000292

Gnomad EAS exome

AF:

0.000997

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00102

GnomAD4 exome

AF:

0.0000430

AC:

AN:

1348762

Hom.:

AF XY:

0.0000391

AC XY:

AN XY:

665146

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:

27392

American (AMR)

AF:

0.000382

AC:

AN:

31452

Ashkenazi Jewish (ASJ)

AF:

0.000126

AC:

AN:

23838

East Asian (EAS)

AF:

0.000252

AC:

AN:

31798

South Asian (SAS)

AF:

0.0000793

AC:

AN:

75706

European-Finnish (FIN)

AF:

0.0000593

AC:

AN:

33710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4010

European-Non Finnish (NFE)

AF:

0.0000169

AC:

AN:

1064752

Other (OTH)

AF:

0.000160

AC:

AN:

56104

⚠️ 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: 0.266

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74186

African (AFR)

AF:

0.00

AC:

AN:

41358

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67944

Other (OTH)

AF:

0.00

AC:

AN:

2088

Alfa

AF:

0.000612

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinoblastoma (3)

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over