13-48303925-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000321.3(RB1):​c.13A>G​(p.Thr5Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000519 in 1,347,594 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. T5S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08283746).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.13A>G	p.Thr5Ala	missense	Exon 1 of 27	NP_000312.2
	RB1	NM_001407165.1		c.13A>G	p.Thr5Ala	missense	Exon 1 of 27	NP_001394094.1
	RB1	NM_001407166.1		c.13A>G	p.Thr5Ala	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.13A>G	p.Thr5Ala	missense	Exon 1 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.13A>G		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1
	RB1	ENST00000650461.1		c.13A>G	p.Thr5Ala	missense	Exon 1 of 27	ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000519 AC: 7 AN: 1347594 Hom.: 0 Cov.: 31 AF XY: 0.00000601 AC XY: 4 AN XY: 665150

African (AFR) AF: 0.00 AC: 0 AN: 27422

American (AMR) AF: 0.00 AC: 0 AN: 33014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23648

East Asian (EAS) AF: 0.00 AC: 0 AN: 31552

South Asian (SAS) AF: 0.00 AC: 0 AN: 76610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3928

European-Non Finnish (NFE) AF: 0.00000659 AC: 7 AN: 1062176

Other (OTH) AF: 0.00 AC: 0 AN: 55862

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:1

Apr 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 5 of the RB1 protein (p.Thr5Ala). 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: 860944). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T5A variant (also known as c.13A>G), located in coding exon 1 of the RB1 gene, results from an A to G substitution at nucleotide position 13. The threonine at codon 5 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.52
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.29	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.38
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.20
Sift	Benign	0.41	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.067
MutPred		0.34		Gain of catalytic residue at P2 (P = 0)
MVP		0.62
MPC		0.43
ClinPred		0.093	T
GERP RS		-3.0
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.10
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: rs898303682; hg19: chr13-48878061;