Genetic Variant RB1:p.Ala15Pro (chr13-48303955-G-C) – 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.43G>C(p.Ala15Pro) 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. 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. A15T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 0.438

Publications

2 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=0.1119453).

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.43G>C	p.Ala15Pro	missense	Exon 1 of 27	NP_000312.2
RB1	NM_001407165.1		c.43G>C	p.Ala15Pro	missense	Exon 1 of 27	NP_001394094.1
RB1	NM_001407166.1		c.43G>C	p.Ala15Pro	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.43G>C	p.Ala15Pro	missense	Exon 1 of 27	ENSP00000267163.4
RB1	ENST00000467505.6	TSL:1	n.43G>C		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1
RB1	ENST00000650461.1		c.43G>C	p.Ala15Pro	missense	Exon 1 of 27	ENSP00000497193.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

May 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A15P variant (also known as c.43G>C), located in coding exon 1 of the RB1 gene, results from a G to C substitution at nucleotide position 43. The alanine at codon 15 is replaced by proline, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.34

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.0

PhyloP100

0.44

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.42

REVEL

Benign

0.14

Sift

Benign

0.28

Sift4G

Benign

0.28

Polyphen

0.0

Vest4

0.23

MutPred

0.37

Gain of catalytic residue at P20 (P = 6e-04)

MVP

0.55

MPC

0.58

ClinPred

0.091

GERP RS

0.54

PromoterAI

-0.018

Neutral

(source)

Varity_R

0.13

gMVP

0.31

Mutation Taster

=91/9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over