13-48303944-C-G

Variant names:

• chr13-48303944-C-G
• rs899323337
• NM_000321.3:c.32C>G

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.32C>G​(p.Ala11Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,357,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A11T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.97
• Publications: 0 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=0.09120247).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.32C>G	p.Ala11Gly	missense	Exon 1 of 27	NP_000312.2
	RB1	NM_001407165.1		c.32C>G	p.Ala11Gly	missense	Exon 1 of 27	NP_001394094.1
	RB1	NM_001407166.1		c.32C>G	p.Ala11Gly	missense	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.32C>G	p.Ala11Gly	missense	Exon 1 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.32C>G		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1
	RB1	ENST00000650461.1		c.32C>G	p.Ala11Gly	missense	Exon 1 of 27	ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000295 AC: 4 AN: 1357590 Hom.: 0 Cov.: 31 AF XY: 0.00000448 AC XY: 3 AN XY: 669668

African (AFR) AF: 0.00 AC: 0 AN: 27782

American (AMR) AF: 0.00 AC: 0 AN: 33266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24204

East Asian (EAS) AF: 0.00 AC: 0 AN: 32412

South Asian (SAS) AF: 0.00 AC: 0 AN: 76622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34146

Middle Eastern (MID) AF: 0.000249 AC: 1 AN: 4010

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068592

Other (OTH) AF: 0.0000530 AC: 3 AN: 56556

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

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 11 of the RB1 protein (p.Ala11Gly). 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: 527927). 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. 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.

Jul 20, 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 alanine with glycine at codon 11 of the RB1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RB1-related disorders 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

May 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A11G variant (also known as c.32C>G), located in coding exon 1 of the RB1 gene, results from a C to G substitution at nucleotide position 32. The alanine at codon 11 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	13
DANN	Benign	0.65
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.76
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.060	N
REVEL	Benign	0.081
Sift	Benign	0.57	T
Sift4G	Benign	0.56	T
Polyphen		0.030	B
Vest4		0.18
MutPred		0.29		Loss of helix (P = 0.0068)
MVP		0.70
MPC		0.44
ClinPred		0.12	T
GERP RS		3.4
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.073
gMVP		0.16
Mutation Taster		=93/7	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: rs899323337; hg19: chr13-48878080;