chr13-48303995-C-G

Position:

chr13-48303995-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000321.3(RB1):c.83C>G(p.Pro28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000734 in 1,497,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000074 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.83

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 (HGNC:):

RB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22711235).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3 linkuse as main transcript	c.83C>G	p.Pro28Arg	missense_variant	1/27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 linkuse as main transcript	c.83C>G	p.Pro28Arg	missense_variant	1/27		NP_001394094.1
RB1	NM_001407166.1 linkuse as main transcript	c.83C>G	p.Pro28Arg	missense_variant	1/17		NP_001394095.1
RB1	NM_001407167.1 linkuse as main transcript	c.83C>G	p.Pro28Arg	missense_variant	1/3		NP_001394096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 linkuse as main transcript	c.83C>G	p.Pro28Arg	missense_variant	1/27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000107

AC:

AN:

93876

Hom.:

AF XY:

0.00

AC XY:

AN XY:

53034

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000539

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000743

AC:

AN:

1345604

Hom.:

Cov.:

AF XY:

0.00000904

AC XY:

AN XY:

663668

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000530

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000107

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000176

AC:

Asia WGS

AF:

0.000580

AC:

AN:

3460

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinoblastoma

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This missense variant replaces proline with arginine at codon 28 of the RB1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with retinoblastoma in the literature (PMID: 30636860, 34277001), however in one of those patients the variant co-occurred with an RB1 duplication of exon 12, which more likely explains the disease phenotype (PMID: 34277001). This variant has been identified in 1/93876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.0090

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.27

T;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.46

T;T;T

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Uncertain

-0.056

MutationAssessor

Benign

0.34

N;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.030

N;.;.

REVEL

Benign

0.23

Sift

Uncertain

0.028

D;.;.

Sift4G

Uncertain

0.019

D;.;.

Polyphen

0.15

B;.;.

Vest4

0.37

MutPred

0.29

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

0.80

MPC

0.47

ClinPred

0.24

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.098

gMVP

0.17

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over