13-48465008-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000321.3(RB1):c.2222G>T(p.Arg741Leu) variant causes a missense change. 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. R741H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 24)

Exomes 𝑓: 9.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.66

Publications

1 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 25 uncertain in NM_000321.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.2222G>T	p.Arg741Leu	missense_variant	Exon 22 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.2222G>T	p.Arg741Leu	missense_variant	Exon 22 of 27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.2222G>T	p.Arg741Leu	missense_variant	Exon 22 of 27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111640

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000408

AC:

AN:

245098

AF XY:

0.00000754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000561

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.93e-7

AC:

AN:

1007322

Hom.:

Cov.:

AF XY:

0.00000196

AC XY:

AN XY:

511228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26394

American (AMR)

AF:

0.00

AC:

AN:

38846

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18800

East Asian (EAS)

AF:

0.0000364

AC:

AN:

27486

South Asian (SAS)

AF:

0.00

AC:

AN:

74216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3128

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

733960

Other (OTH)

AF:

0.00

AC:

AN:

40894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

111710

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

50916

African (AFR)

AF:

0.00

AC:

AN:

30000

American (AMR)

AF:

0.00

AC:

AN:

8120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3078

East Asian (EAS)

AF:

0.00

AC:

AN:

3634

South Asian (SAS)

AF:

0.00

AC:

AN:

3550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

114

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

57652

Other (OTH)

AF:

0.00

AC:

AN:

1430

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R741L variant (also known as c.2222G>T), located in coding exon 22 of the RB1 gene, results from a G to T substitution at nucleotide position 2222. The arginine at codon 741 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

1.0

L;.

PhyloP100

4.7

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.3

D;.

REVEL

Uncertain

0.60

Sift

Benign

0.034

D;.

Sift4G

Benign

0.24

T;.

Polyphen

0.76

P;.

Vest4

0.69

MutPred

0.60

Gain of ubiquitination at K740 (P = 0.0435);Gain of ubiquitination at K740 (P = 0.0435);

MVP

0.93

MPC

0.77

ClinPred

0.91

GERP RS

5.5

Varity_R

0.86

gMVP

0.63

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over