Genetic Variant RB1:p.Leu220Val (chr13-48360067-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_000321.3(RB1):c.658C>G(p.Leu220Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L220I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.342

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 13-48360067-C-G is Pathogenic according to our data. Variant chr13-48360067-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1678695.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RB1	NM_000321.3 link	c.658C>G	p.Leu220Val	missense_variant	Exon 7 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1 link	c.658C>G	p.Leu220Val	missense_variant	Exon 7 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.658C>G	p.Leu220Val	missense_variant	Exon 7 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.658C>G	p.Leu220Val	missense_variant	Exon 7 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Mar 05, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19339519, 21654082, 25151137, 18181215, 18449911, 17996702, 30031154, 28575107, 31997559, 23516486) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.

Eigen

Benign

-0.036

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.85

D;D

M_CAP

Benign

0.051

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

0.34

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.7

N;.

REVEL

Pathogenic

0.74

Sift

Benign

0.042

D;.

Sift4G

Benign

0.072

T;.

Polyphen

0.98

D;.

Vest4

0.73

MutPred

0.38

Gain of catalytic residue at M219 (P = 0);Gain of catalytic residue at M219 (P = 0);

MVP

0.77

MPC

1.3

ClinPred

0.93

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.46

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.99

Position offset: -1

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over