13-48364937-C-G

Position:

• chr13-48364937-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BS2_Supporting

The NM_000321.3(RB1):​c.905C>G​(p.Ser302Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000352 in 1,418,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.905C>G	p.Ser302Cys	missense_variant	9/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.905C>G	p.Ser302Cys	missense_variant	9/27		NP_001394094.1
RB1	NM_001407166.1	c.905C>G	p.Ser302Cys	missense_variant	9/17		NP_001394095.1
LOC112268118	XR_002957522.2	n.161G>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.905C>G	p.Ser302Cys	missense_variant	9/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.905C>G	p.Ser302Cys	missense_variant	9/27			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1418484 Hom.: 0 Cov.: 30 AF XY: 0.00000285 AC XY: 2 AN XY: 702190

Gnomad4 AFR exome AF: 0.00

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: 0.00000368

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 2022

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) performed at Invitae indicates that this missense variant is expected to disrupt RB1 protein function. 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). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 302 of the RB1 protein (p.Ser302Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.0060	D;.
Polyphen		1.0	D;.
Vest4		0.66
MutPred		0.51		Gain of catalytic residue at M300 (P = 0);Gain of catalytic residue at M300 (P = 0);
MVP		0.86
MPC		1.3
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.45
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-48939073;