Genetic Variant RB1:p.Gly310Val (chr13-48364961-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000321.3(RB1):c.929G>T(p.Gly310Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G310E) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.53

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RB1	NM_000321.3 link	c.929G>T	p.Gly310Val	missense_variant	Exon 9 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1 link	c.929G>T	p.Gly310Val	missense_variant	Exon 9 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.929G>T	p.Gly310Val	missense_variant	Exon 9 of 17		NP_001394095.1
LOC112268118	XR_002957522.2 link	n.137C>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.929G>T	p.Gly310Val	missense_variant	Exon 9 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1418772

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702492

African (AFR)

AF:

0.00

AC:

AN:

31956

American (AMR)

AF:

0.00

AC:

AN:

42050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25312

East Asian (EAS)

AF:

0.00

AC:

AN:

37588

South Asian (SAS)

AF:

0.00

AC:

AN:

81570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5360

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086074

Other (OTH)

AF:

0.00

AC:

AN:

58274

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

2.0

M;.

PhyloP100

3.5

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.69

Sift

Benign

0.069

T;.

Sift4G

Benign

0.071

T;.

Polyphen

1.0

D;.

Vest4

0.80

MutPred

0.47

Gain of catalytic residue at G310 (P = 0.0145);Gain of catalytic residue at G310 (P = 0.0145);

MVP

0.87

MPC

1.1

ClinPred

0.94

GERP RS

4.7

Varity_R

0.53

gMVP

0.78

Mutation Taster

=59/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

Computational scores

Splicing

Publications

Other links and lift over