13-48307377-G-C

Variant names:

• chr13-48307377-G-C
• rs1060503090
• NM_000321.3:c.235G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000321.3(RB1):​c.235G>C​(p.Glu79Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.20

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16095877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.235G>C	p.Glu79Gln	missense_variant	Exon 2 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.235G>C	p.Glu79Gln	missense_variant	Exon 2 of 27		NP_001394094.1
RB1	NM_001407166.1	c.235G>C	p.Glu79Gln	missense_variant	Exon 2 of 17		NP_001394095.1
RB1	NM_001407167.1	c.235G>C	p.Glu79Gln	missense_variant	Exon 2 of 3		NP_001394096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.235G>C	p.Glu79Gln	missense_variant	Exon 2 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461172 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726938

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:1

Nov 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 79 of the RB1 protein (p.Glu79Gln). 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: 410946). 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) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function with a negative predictive value of 80%. 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. -

Malignant tumor of urinary bladder Uncertain:1

Sep 10, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Mar 01, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23516486) -

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 02, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E79Q variant (also known as c.235G>C), located in coding exon 2 of the RB1 gene, results from a G to C substitution at nucleotide position 235. The glutamic acid at codon 79 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.63	N;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.50	N;.;.
REVEL	Benign	0.052
Sift	Benign	0.14	T;.;.
Sift4G	Benign	0.32	T;.;.
Polyphen		0.013	B;.;.
Vest4		0.39
MutPred		0.37		Gain of catalytic residue at L76 (P = 5e-04);Gain of catalytic residue at L76 (P = 5e-04);Gain of catalytic residue at L76 (P = 5e-04);
MVP		0.65
MPC		0.44
ClinPred		0.39	T
GERP RS		3.1
Varity_R		0.20
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs1060503090; hg19: chr13-48881513;