13-48368550-G-T

Variant names:

• chr13-48368550-G-T
• NM_000321.3:c.1073G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000321.3(RB1):​c.1073G>T​(p.Arg358Leu) 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. 13/21 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. R358G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.460

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]

LOC112268118 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09927526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1073G>T	p.Arg358Leu	missense_variant	Exon 11 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1073G>T	p.Arg358Leu	missense_variant	Exon 11 of 27		NP_001394094.1
RB1	NM_001407166.1	c.1073G>T	p.Arg358Leu	missense_variant	Exon 11 of 17		NP_001394095.1
LOC112268118	XR_002957522.2	n.122-3574C>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1073G>T	p.Arg358Leu	missense_variant	Exon 11 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1073G>T	p.Arg358Leu	missense_variant	Exon 11 of 27			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 11, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R358L variant (also known as c.1073G>T), located in coding exon 11 of the RB1 gene, results from a G to T substitution at nucleotide position 1073. The arginine at codon 358 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Uncertain	0.43	T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.6	N;.
REVEL	Uncertain	0.42
Sift	Benign	0.21	T;.
Sift4G	Uncertain	0.046	D;.
Polyphen		0.23	B;.
Vest4		0.27
MutPred		0.42		Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);
MVP		0.85
MPC		0.55
ClinPred		0.23	T
GERP RS		-2.0
Varity_R		0.073
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-48942686;