Genetic Variant NM_000321.3:c.109A>T (chr13-48304021-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000321.3(RB1):c.109A>T(p.Ser37Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. S37G) has been classified as Likely 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: 1.85

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24508154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.109A>T	p.Ser37Cys	missense_variant	Exon 1 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.109A>T	p.Ser37Cys	missense_variant	Exon 1 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.109A>T	p.Ser37Cys	missense_variant	Exon 1 of 17		NP_001394095.1
RB1	NM_001407167.1 link	c.109A>T	p.Ser37Cys	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.109A>T	p.Ser37Cys	missense_variant	Exon 1 of 27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1315728

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

648602

African (AFR)

AF:

0.00

AC:

AN:

26316

American (AMR)

AF:

0.00

AC:

AN:

24110

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22694

East Asian (EAS)

AF:

0.00

AC:

AN:

29472

South Asian (SAS)

AF:

0.00

AC:

AN:

71504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3970

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1050220

Other (OTH)

AF:

0.00

AC:

AN:

54598

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.37

T;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.060

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.63

T;T;T

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

0.63

N;.;.

PhyloP100

1.9

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.68

N;.;.

REVEL

Uncertain

0.35

Sift

Uncertain

0.018

D;.;.

Sift4G

Uncertain

0.021

D;.;.

Polyphen

0.99

D;.;.

Vest4

0.22

MutPred

0.23

Loss of glycosylation at S37 (P = 0.0043);Loss of glycosylation at S37 (P = 0.0043);Loss of glycosylation at S37 (P = 0.0043);

MVP

0.82

MPC

0.55

ClinPred

0.45

GERP RS

2.6

PromoterAI

0.049

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.17

gMVP

0.23

Mutation Taster

=91/9

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over