rs766529534

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 2P and 14B. PM1BP4_ModerateBP6_Very_StrongBS2

The NM_000321.3(RB1):c.113G>A(p.Gly38Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,464,720 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G38S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.38

Publications

3 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: Benign. The variant received -12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 38 uncertain in NM_000321.3

BP4

Computational evidence support a benign effect (MetaRNN=0.11763701).

BP6

Variant 13-48304025-G-A is Benign according to our data. Variant chr13-48304025-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 410930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.113G>A	p.Gly38Asp	missense_variant	Exon 1 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.113G>A	p.Gly38Asp	missense_variant	Exon 1 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.113G>A	p.Gly38Asp	missense_variant	Exon 1 of 17		NP_001394095.1
RB1	NM_001407167.1 link	c.113G>A	p.Gly38Asp	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.113G>A	p.Gly38Asp	missense_variant	Exon 1 of 27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000159

AC:

AN:

69018

AF XY:

0.000198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000857

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000187

AC:

245

AN:

1312602

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

125

AN XY:

646844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26236

American (AMR)

AF:

0.0000850

AC:

AN:

23534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22586

East Asian (EAS)

AF:

0.00

AC:

AN:

29268

South Asian (SAS)

AF:

0.000492

AC:

AN:

71082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3962

European-Non Finnish (NFE)

AF:

0.000194

AC:

203

AN:

1048706

Other (OTH)

AF:

0.0000918

AC:

AN:

54440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000145

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.000196

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000324

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.0000791

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Benign:2

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Nov 03, 2020

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Aug 10, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

RB1-related disorder

Benign:1

Mar 02, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.28

T;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.58

T;T;T

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.55

N;.;.

PhyloP100

3.4

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.34

N;.;.

REVEL

Benign

0.23

Sift

Benign

0.33

T;.;.

Sift4G

Benign

0.081

T;.;.

Polyphen

0.0010

B;.;.

Vest4

0.36

MVP

0.75

MPC

0.58

ClinPred

0.14

GERP RS

2.9

PromoterAI

0.041

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.11

gMVP

0.38

Mutation Taster

=89/11

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over