13-48364937-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000321.3(RB1):c.905C>T(p.Ser302Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S302Y) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.61

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:

LOC112268118 (HGNC:):

LOC112268118 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.905C>T	p.Ser302Phe	missense_variant	Exon 9 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.905C>T	p.Ser302Phe	missense_variant	Exon 9 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.905C>T	p.Ser302Phe	missense_variant	Exon 9 of 17		NP_001394095.1
LOC112268118	XR_002957522.2 link	n.161G>A		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.905C>T	p.Ser302Phe	missense_variant	Exon 9 of 27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1418484

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702190

African (AFR)

AF:

0.00

AC:

AN:

31920

American (AMR)

AF:

0.00

AC:

AN:

41826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25348

East Asian (EAS)

AF:

0.00

AC:

AN:

37572

South Asian (SAS)

AF:

0.00

AC:

AN:

81648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5514

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085836

Other (OTH)

AF:

0.00

AC:

AN:

58284

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41384

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Uncertain:2

Feb 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 302 of the RB1 protein (p.Ser302Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 822951). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces serine with phenylalanine at codon 302 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Oct 23, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S302F variant (also known as c.905C>T), located in coding exon 9 of the RB1 gene, results from a C to T substitution at nucleotide position 905. The serine at codon 302 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Benign

0.20

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

5.6

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.0

N;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0050

D;.

Sift4G

Benign

0.093

T;.

Polyphen

1.0

D;.

Vest4

0.79

MutPred

0.48

Gain of catalytic residue at N301 (P = 0.0021);Gain of catalytic residue at N301 (P = 0.0021);

MVP

0.87

MPC

1.4

ClinPred

0.96

GERP RS

5.6

Varity_R

0.58

gMVP

0.57

Mutation Taster

=37/63

disease causing

(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

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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