13-48348994-T-C

Position:

• chr13-48348994-T-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.578T>C​(p.Val193Ala) 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. 15/21 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)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.08

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]

RB1 (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=0.16211316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.578T>C	p.Val193Ala	missense_variant	6/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.578T>C	p.Val193Ala	missense_variant	6/27		NP_001394094.1
RB1	NM_001407166.1	c.578T>C	p.Val193Ala	missense_variant	6/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.578T>C	p.Val193Ala	missense_variant	6/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000467505.5	n.138-11023T>C		intron_variant		1		ENSP00000434702.1
RB1	ENST00000650461.1	c.578T>C	p.Val193Ala	missense_variant	6/27			ENSP00000497193.1
RB1	ENST00000525036.1	n.740T>C		non_coding_transcript_exon_variant	6/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 05, 2022

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 193 of the RB1 protein (p.Val193Ala). 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. ClinVar contains an entry for this variant (Variation ID: 410953). 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). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The p.V193A variant (also known as c.578T>C), located in coding exon 6 of the RB1 gene, results from a T to C substitution at nucleotide position 578. The valine at codon 193 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. 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	0.16
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.087
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.55	N;.
REVEL	Benign	0.15
Sift	Benign	0.34	T;.
Sift4G	Benign	0.40	T;.
Polyphen		0.024	B;.
Vest4		0.26
MutPred		0.58		Gain of catalytic residue at V193 (P = 0.0168);Gain of catalytic residue at V193 (P = 0.0168);
MVP		0.78
MPC		0.54
ClinPred		0.19	T
GERP RS		4.8
Varity_R		0.23
gMVP		0.17

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: rs1060503093; hg19: chr13-48923130;