chr13-48381367-G-A

Variant names:

• chr13-48381367-G-A
• NM_000321.3:c.1619G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000321.3(RB1):​c.1619G>A​(p.Gly540Asp) variant causes a missense change. 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: 3.91

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 2 ACMG points.

• PM1: In a region_of_interest Domain A (size 206) in uniprot entity RB_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1786522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1619G>A	p.Gly540Asp	missense_variant	Exon 17 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1619G>A	p.Gly540Asp	missense_variant	Exon 17 of 27		NP_001394094.1
RB1	NM_001407166.1	c.1619G>A	p.Gly540Asp	missense_variant	Exon 17 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1619G>A	p.Gly540Asp	missense_variant	Exon 17 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1619G>A	p.Gly540Asp	missense_variant	Exon 17 of 27			ENSP00000497193.1
RB1	ENST00000643064.1	c.116G>A	p.Gly39Asp	missense_variant	Exon 1 of 2			ENSP00000496005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Oct 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 540 of the RB1 protein (p.Gly540Asp). 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: 1776555). 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. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G540D variant (also known as c.1619G>A), located in coding exon 17 of the RB1 gene, results from a G to A substitution at nucleotide position 1619. The glycine at codon 540 is replaced by aspartic acid, 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	0.13
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.76
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-1.4	N;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.4	N;.
REVEL	Benign	0.28
Sift	Benign	0.38	T;.
Sift4G	Uncertain	0.0050	D;.
Polyphen		0.0050	B;.
Vest4		0.21
MutPred		0.50		Gain of catalytic residue at I536 (P = 0.0037);Gain of catalytic residue at I536 (P = 0.0037);
MVP		0.54
MPC		0.58
ClinPred		0.67	D
GERP RS		3.5
Varity_R		0.12
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr13-48955503;