13-48364930-A-G

Position:

• chr13-48364930-A-G

Variant summary

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

The NM_000321.3(RB1):​c.898A>G​(p.Met300Val) 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. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20724505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.898A>G	p.Met300Val	missense_variant	9/27	ENST00000267163.6	NP_000312.2
LOC112268118	XR_002957522.2	n.168T>C		non_coding_transcript_exon_variant	3/3
RB1	NM_001407165.1	c.898A>G	p.Met300Val	missense_variant	9/27		NP_001394094.1
RB1	NM_001407166.1	c.898A>G	p.Met300Val	missense_variant	9/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.898A>G	p.Met300Val	missense_variant	9/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1	c.898A>G	p.Met300Val	missense_variant	9/27			ENSP00000497193

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1416942 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 701190

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jan 11, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RB1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 300 of the RB1 protein (p.Met300Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.0033
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.88	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.80	N;.
REVEL	Benign	0.26
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		0.0	B;.
Vest4		0.42
MutPred		0.44		Gain of catalytic residue at S302 (P = 0.0027);Gain of catalytic residue at S302 (P = 0.0027);
MVP		0.79
MPC		0.45
ClinPred		0.58	D
GERP RS		4.3
Varity_R		0.41
gMVP		0.61

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: rs1060503086; hg19: chr13-48939066;