rs896487590

Variant names:

Your query was ambiguous. Multiple possible variants found:

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>C(p.Ser37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,315,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in 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: 0.0000015 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

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

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:

Genome browser will be placed here

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=0.20280349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.109A>C	p.Ser37Arg	missense_variant	Exon 1 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.109A>C	p.Ser37Arg	missense_variant	Exon 1 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.109A>C	p.Ser37Arg	missense_variant	Exon 1 of 17		NP_001394095.1
RB1	NM_001407167.1 link	c.109A>C	p.Ser37Arg	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>C	p.Ser37Arg	missense_variant	Exon 1 of 27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000152

AC:

AN:

1315728

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

648602

show subpopulations

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:

9.52e-7

AC:

AN:

1050220

Other (OTH)

AF:

0.0000183

AC:

AN:

54598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Uncertain:2

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

- -

Sep 09, 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 arginine, which is basic and polar, at codon 37 of the RB1 protein (p.Ser37Arg). 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: 527902). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RB1 protein function. 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S37R variant (also known as c.109A>C), located in coding exon 1 of the RB1 gene, results from an A to C substitution at nucleotide position 109. The serine at codon 37 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.29

T;.;.

Eigen

Benign

-0.061

Eigen_PC

Benign

-0.064

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.67

T;T;T

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Uncertain

0.068

MutationAssessor

Benign

0.97

L;.;.

PhyloP100

1.9

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.18

N;.;.

REVEL

Benign

0.19

Sift

Benign

0.14

T;.;.

Sift4G

Benign

0.12

T;.;.

Polyphen

0.84

P;.;.

Vest4

0.26

MutPred

0.25

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

0.81

MPC

0.53

ClinPred

0.56

GERP RS

2.6

PromoterAI

0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.19

gMVP

0.32

Mutation Taster

=89/11

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over