dbSNP rs886043138: RB1:p.Pro6Thr (chr13-48303928-C-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.16C>A(p.Pro6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.398

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 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21161112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.16C>A	p.Pro6Thr	missense_variant	Exon 1 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.16C>A	p.Pro6Thr	missense_variant	Exon 1 of 27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1359592

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

670770

African (AFR)

AF:

0.00

AC:

AN:

27888

American (AMR)

AF:

0.00

AC:

AN:

33512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24274

East Asian (EAS)

AF:

0.00

AC:

AN:

32602

South Asian (SAS)

AF:

0.00

AC:

AN:

76852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4010

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1069346

Other (OTH)

AF:

0.00

AC:

AN:

56670

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.41

T;.;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.70

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.57

T;T;T

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.55

N;.;.

PhyloP100

0.40

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.1

N;.;.

REVEL

Benign

0.14

Sift

Benign

0.049

D;.;.

Sift4G

Benign

0.083

T;.;.

Polyphen

0.0

B;.;.

Vest4

0.29

MutPred

0.29

Gain of catalytic residue at P2 (P = 0);Gain of catalytic residue at P2 (P = 0);Gain of catalytic residue at P2 (P = 0);

MVP

0.75

MPC

0.50

ClinPred

0.22

GERP RS

1.1

PromoterAI

0.10

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.10

gMVP

0.42

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over