dbSNP rs776175164: RB1:p.Pro28His (chr13-48303995-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000321.3(RB1):c.83C>A(p.Pro28His) 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. 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. P28L) 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

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.83

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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3004005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.83C>A	p.Pro28His	missense_variant	Exon 1 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.83C>A	p.Pro28His	missense_variant	Exon 1 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.83C>A	p.Pro28His	missense_variant	Exon 1 of 17		NP_001394095.1
RB1	NM_001407167.1 link	c.83C>A	p.Pro28His	missense_variant	Exon 1 of 3		NP_001394096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.83C>A	p.Pro28His	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:

1345604

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

663668

African (AFR)

AF:

0.00

AC:

AN:

27118

American (AMR)

AF:

0.00

AC:

AN:

30504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23684

East Asian (EAS)

AF:

0.00

AC:

AN:

31510

South Asian (SAS)

AF:

0.00

AC:

AN:

75498

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4042

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1063786

Other (OTH)

AF:

0.00

AC:

AN:

55962

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 04, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23516486) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.30

T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.40

T;T;T

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

0.69

N;.;.

PhyloP100

2.8

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.26

N;.;.

REVEL

Uncertain

0.37

Sift

Uncertain

0.012

D;.;.

Sift4G

Uncertain

0.020

D;.;.

Polyphen

0.58

P;.;.

Vest4

0.32

MutPred

0.28

Gain of catalytic residue at P23 (P = 5e-04);Gain of catalytic residue at P23 (P = 5e-04);Gain of catalytic residue at P23 (P = 5e-04);

MVP

0.82

MPC

0.51

ClinPred

0.41

GERP RS

3.8

PromoterAI

0.054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.17

gMVP

0.18

Mutation Taster

=61/39

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over