rs898303682

Variant names:

• chr13-48303925-A-C
• rs898303682
• NM_000321.3:c.13A>C

Your query was ambiguous. Multiple possible variants found:

• chr13-48303925-A-C
• chr13-48303925-A-G
• chr13-48303925-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000321.3(RB1):​c.13A>C​(p.Thr5Pro) 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. 14/22 in silico tools predict a benign 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. T5S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.376
• Publications: 7 publications found

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-DT (HGNC:42778): (RB1 divergent transcript)

ACMG classification

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=0.112885684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.13A>C	p.Thr5Pro	missense_variant	Exon 1 of 27	ENST00000267163.6	NP_000312.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.13A>C	p.Thr5Pro	missense_variant	Exon 1 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000438 AC: 59 AN: 1347404 Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 27 AN XY: 665064

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000109 AC: 3 AN: 27418

American (AMR) AF: 0.0000303 AC: 1 AN: 33010

Ashkenazi Jewish (ASJ) AF: 0.000296 AC: 7 AN: 23640

East Asian (EAS) AF: 0.000190 AC: 6 AN: 31542

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33372

Middle Eastern (MID) AF: 0.000255 AC: 1 AN: 3924

European-Non Finnish (NFE) AF: 0.0000367 AC: 39 AN: 1062046

Other (OTH) AF: 0.0000179 AC: 1 AN: 55848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:2

Aug 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is not present in population databases (gnomAD no frequency). 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. 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) has been performed at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 527924). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 5 of the RB1 protein (p.Thr5Pro). -

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Benign	0.67
DEOGEN2	Benign	0.28	T;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.31	T;T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N;.;.
PhyloP100		0.38
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.35	N;.;.
REVEL	Benign	0.13
Sift	Benign	0.28	T;.;.
Sift4G	Benign	0.38	T;.;.
Polyphen		0.037	B;.;.
Vest4		0.19
MutPred		0.33		Gain of catalytic residue at P2 (P = 0);Gain of catalytic residue at P2 (P = 0);Gain of catalytic residue at P2 (P = 0);
MVP		0.77
MPC		0.58
ClinPred		0.12	T
GERP RS		-3.0
PromoterAI		0.069	Neutral
Varity_R		0.11
gMVP		0.094
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs898303682; hg19: chr13-48878061;