rs183898408

Positions:

• chr13-48364952-C-G
• chr13-48364952-C-T

Variant summary

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

The NM_000321.3(RB1):​c.920C>G​(p.Thr307Arg) 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. 16/21 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. T307I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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=0.17462966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.920C>G	p.Thr307Arg	missense_variant	9/27	ENST00000267163.6
LOC112268118	XR_002957522.2	n.146G>C		non_coding_transcript_exon_variant	3/3
RB1	NM_001407165.1	c.920C>G	p.Thr307Arg	missense_variant	9/27
RB1	NM_001407166.1	c.920C>G	p.Thr307Arg	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.920C>G	p.Thr307Arg	missense_variant	9/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.920C>G	p.Thr307Arg	missense_variant	9/27

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2020

The p.T307R variant (also known as c.920C>G), located in coding exon 9 of the RB1 gene, results from a C to G substitution at nucleotide position 920. The threonine at codon 307 is replaced by arginine, an amino acid with similar properties. This amino acid position is poorly 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	0.14
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.032
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	0.64	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.57	N;.
REVEL	Benign	0.28
Sift	Benign	0.51	T;.
Sift4G	Benign	0.39	T;.
Polyphen		0.0	B;.
Vest4		0.40
MutPred		0.41		Gain of catalytic residue at S302 (P = 0.0014);Gain of catalytic residue at S302 (P = 0.0014);
MVP		0.60
MPC		0.67
ClinPred		0.44	T
GERP RS		5.6
Varity_R		0.27
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr13-48939088;