Genetic Variant RB1:p.Ala15Val (chr13-48303956-C-T) – 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.44C>T(p.Ala15Val) 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. 13/22 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. A15T) has been classified as Uncertain significance.

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: 1.49

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=0.128878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.44C>T	p.Ala15Val	missense_variant	Exon 1 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.44C>T	p.Ala15Val	missense_variant	Exon 1 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.44C>T	p.Ala15Val	missense_variant	Exon 1 of 17		NP_001394095.1
RB1	NM_001407167.1 link	c.44C>T	p.Ala15Val	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.44C>T	p.Ala15Val	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:

1354990

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

668594

African (AFR)

AF:

0.00

AC:

AN:

25690

American (AMR)

AF:

0.00

AC:

AN:

33140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24194

East Asian (EAS)

AF:

0.00

AC:

AN:

32470

South Asian (SAS)

AF:

0.00

AC:

AN:

76648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4024

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1068526

Other (OTH)

AF:

0.00

AC:

AN:

56280

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.30

T;.;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.56

T;T;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.0

N;.;.

PhyloP100

1.5

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.21

N;.;.

REVEL

Benign

0.14

Sift

Benign

0.28

T;.;.

Sift4G

Benign

0.29

T;.;.

Polyphen

0.014

B;.;.

Vest4

0.23

MutPred

0.41

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

MVP

0.72

MPC

0.44

ClinPred

0.10

GERP RS

1.8

PromoterAI

-0.0086

Neutral

(source)

Varity_R

0.031

gMVP

0.18

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