dbSNP rs200658795: RB1:c.1390-11A>G (chr13-48380042-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000321.3(RB1):c.1390-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 1,198,044 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 7 hom., cov: 30)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

RB1
NM_000321.3 intron

Scores

Splicing: ADA: 0.00007313

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 1.05

Publications

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

RB1 links:

LOC112268118 (HGNC:):

LOC112268118 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000321.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 13-48380042-A-G is Benign according to our data. Variant chr13-48380042-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255821.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00336 (481/143254) while in subpopulation AFR AF = 0.012 (466/38948). AF 95% confidence interval is 0.0111. There are 7 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 481 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RB1	NM_000321.3	MANE Select	c.1390-11A>G	intron	N/A	NP_000312.2	P06400
RB1	NM_001407165.1		c.1390-11A>G	intron	N/A	NP_001394094.1	A0A3B3IS71
RB1	NM_001407166.1		c.1390-11A>G	intron	N/A	NP_001394095.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RB1	ENST00000267163.6	TSL:1 MANE Select	c.1390-11A>G	intron	N/A	ENSP00000267163.4	P06400
RB1	ENST00000467505.6	TSL:1	n.*758-11A>G	intron	N/A	ENSP00000434702.1	Q92728
RB1	ENST00000924352.1		c.1513-11A>G	intron	N/A	ENSP00000594411.1

Frequencies

GnomAD3 genomes

AF:

0.00337

AC:

483

AN:

143206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000354

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000220

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000910

Gnomad OTH

AF:

0.00204

GnomAD2 exomes

AF:

0.000596

AC:

AN:

114180

AF XY:

0.000530

show subpopulations

Gnomad AFR exome

AF:

0.00833

Gnomad AMR exome

AF:

0.000481

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000837

Gnomad OTH exome

AF:

0.00142

GnomAD4 exome

AF:

0.000306

AC:

323

AN:

1054790

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

135

AN XY:

526366

show subpopulations

African (AFR)

AF:

0.0107

AC:

228

AN:

21274

American (AMR)

AF:

0.000793

AC:

AN:

18918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17648

East Asian (EAS)

AF:

0.00

AC:

AN:

24758

South Asian (SAS)

AF:

0.0000335

AC:

AN:

59688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37000

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

2870

European-Non Finnish (NFE)

AF:

0.0000265

AC:

AN:

830796

Other (OTH)

AF:

0.00127

AC:

AN:

41838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

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

AF:

0.00336

AC:

481

AN:

143254

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

221

AN XY:

69490

show subpopulations

African (AFR)

AF:

0.0120

AC:

466

AN:

38948

American (AMR)

AF:

0.000353

AC:

AN:

14148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3378

East Asian (EAS)

AF:

0.00

AC:

AN:

4940

South Asian (SAS)

AF:

0.00

AC:

AN:

4532

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000910

AC:

AN:

65920

Other (OTH)

AF:

0.00202

AC:

AN:

1978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00274

Hom.:

Bravo

AF:

0.00379

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinoblastoma (4)

not provided (2)

Hereditary cancer-predisposing syndrome (1)

Hereditary retinoblastoma (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000073

dbscSNV1_RF

Benign

0.084

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over