rs1131690864

Variant names:

• chr13-48362953-A-G
• rs1131690864
• NM_000321.3:c.857A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-48362953-A-G
• chr13-48362953-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000321.3(RB1):​c.857A>G​(p.Asp286Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.37

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-48362953-A-G is Pathogenic according to our data. Variant chr13-48362953-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.857A>G	p.Asp286Gly	missense_variant	Exon 8 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.857A>G	p.Asp286Gly	missense_variant	Exon 8 of 27		NP_001394094.1
RB1	NM_001407166.1	c.857A>G	p.Asp286Gly	missense_variant	Exon 8 of 17		NP_001394095.1
LOC112268118	XR_002957522.2	n.*235T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.857A>G	p.Asp286Gly	missense_variant	Exon 8 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.857A>G	p.Asp286Gly	missense_variant	Exon 8 of 27			ENSP00000497193.1
RB1	ENST00000467505.5	n.*225A>G		downstream_gene_variant		1		ENSP00000434702.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:2

May 20, 2024

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PM2 -

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 286 of the RB1 protein (p.Asp286Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinoblastoma (PMID: 23532519; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 428682). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RB1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 05, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

​The p.D286G variant (also known as c.857A>G) is located in coding exon 8 of the RB1 gene. This alteration results from an A to G substitution at nucleotide position 857. The aspartic acid at codon 286 is replaced by glycine, an amino acid with similar properties. This alteration has been detected in a 12-year-old Brazilian female with bilateral retinoblastoma and also a 3-year-old female with bilateral retinoblastoma (Barbosa RH et al. Invest Ophthalmol Vis Sci. 2013 May 7;54(5):3184-94; Dommering CJ et al. Fertil. Steril. 2012 Jan;97(1):79-81). This variant co-segregated with disease in 3 individuals from one family tested in our laboratory (Ambry internal data). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, <span style="font-family:arial,sans-serif; font-size:10pt">the <span style="font-family:arial,sans-serif">in silico prediction for this alteration is inconclusive. Using the HSF and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.65
Sift	Benign	0.067	T;.
Sift4G	Uncertain	0.0070	D;.
Polyphen		1.0	D;.
Vest4		0.49
MutPred		0.41		Gain of catalytic residue at N284 (P = 0.0059);Gain of catalytic residue at N284 (P = 0.0059);
MVP		0.86
MPC		1.1
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.53
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1131690864; hg19: chr13-48937089; COSMIC: COSV104565271; COSMIC: COSV104565271;