rs587778640

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BS2_Supporting

The NM_000321.3(RB1):c.1573G>A(p.Ala525Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,611,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:3O:1

Conservation

PhyloP100: 7.72

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a region_of_interest Domain A (size 206) in uniprot entity RB_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000321.3

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3 linkuse as main transcript	c.1573G>A	p.Ala525Thr	missense_variant	17/27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 linkuse as main transcript	c.1573G>A	p.Ala525Thr	missense_variant	17/27		NP_001394094.1
RB1	NM_001407166.1 linkuse as main transcript	c.1573G>A	p.Ala525Thr	missense_variant	17/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RB1	ENST00000267163.6 linkuse as main transcript	c.1573G>A	p.Ala525Thr	missense_variant	17/27	1	NM_000321.3	ENSP00000267163.4	P06400
RB1	ENST00000650461.1 linkuse as main transcript	c.1573G>A	p.Ala525Thr	missense_variant	17/27			ENSP00000497193.1	A0A3B3IS71
RB1	ENST00000643064.1 linkuse as main transcript	c.70G>A	p.Ala24Thr	missense_variant	1/2			ENSP00000496005.1	A0A2R8Y743

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151946

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:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000602

AC:

AN:

249180

Hom.:

AF XY:

0.0000817

AC XY:

AN XY:

134612

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.000265

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1459934

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.000198

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151946

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000284

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3470

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinoblastoma

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces alanine with threonine at codon 525 of the RB1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with unilateral retinoblastoma but was also found in their unaffected parent and in other asymptomatic individuals (PMID: 24728327, 34680218). This variant has been identified in 15/249180 chromosomes in the general population by the Genome Aggregation Database (gnomAD), suggesting the variant frequency is greater than expected for the disease. 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	Oct 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Ovarian cancer

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in an individual with unilateral retinoblastoma as well as their unaffected parent (Alekseeva et al., 2021); Observed in an individual with stomach cancer, as well as healthy individuals undergoing whole genome sequencing (Bodian et al., 2014; Huang et al., 2018); This variant is associated with the following publications: (PMID: 24728327, 34680218, 36451132, 29625052) -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

This alteration is classified as 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. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.5

D;.

REVEL

Pathogenic

0.86

Sift

Benign

0.033

D;.

Sift4G

Uncertain

0.0090

D;.

Polyphen

1.0

D;.

Vest4

0.89

MutPred

0.72

Gain of catalytic residue at K524 (P = 5e-04);Gain of catalytic residue at K524 (P = 5e-04);

MVP

0.91

MPC

1.1

ClinPred

0.26

GERP RS

5.3

Varity_R

0.93

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 19

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