dbSNP rs528218090: RB1:p.Ala18Thr (chr13-48303964-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000321.3(RB1):c.52G>A(p.Ala18Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,357,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A18S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.48

Publications

13 publications found

Variant links:

COSMIC-nc: COSV57307308

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11885232).

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
RB1	NM_000321.3	MANE Select	c.52G>A	p.Ala18Thr	missense	Exon 1 of 27	NP_000312.2
RB1	NM_001407165.1		c.52G>A	p.Ala18Thr	missense	Exon 1 of 27	NP_001394094.1
RB1	NM_001407166.1		c.52G>A	p.Ala18Thr	missense	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RB1	ENST00000267163.6	TSL:1 MANE Select	c.52G>A	p.Ala18Thr	missense	Exon 1 of 27	ENSP00000267163.4
RB1	ENST00000467505.6	TSL:1	n.52G>A		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1
RB1	ENST00000924352.1		c.52G>A	p.Ala18Thr	missense	Exon 1 of 28	ENSP00000594411.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.37e-7

AC:

AN:

1357622

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

669730

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27790

American (AMR)

AF:

0.00

AC:

AN:

33330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24200

East Asian (EAS)

AF:

0.00

AC:

AN:

32536

South Asian (SAS)

AF:

0.0000130

AC:

AN:

76678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4032

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1068540

Other (OTH)

AF:

0.00

AC:

AN:

56558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinoblastoma (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.28

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.70

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.49

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.55

PhyloP100

1.5

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.0

REVEL

Benign

0.13

Sift

Benign

0.58

Sift4G

Benign

0.63

Polyphen

0.046

Vest4

0.14

MutPred

0.36

Gain of phosphorylation at A18 (P = 5e-04)

MVP

0.78

MPC

0.43

ClinPred

0.15

GERP RS

3.0

PromoterAI

0.061

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.038

gMVP

0.19

Mutation Taster

=98/2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over