rs1131690864

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.857A>G	p.Asp286Gly	missense_variant	8/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.857A>G	p.Asp286Gly	missense_variant	8/27		NP_001394094.1
RB1	NM_001407166.1	c.857A>G	p.Asp286Gly	missense_variant	8/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.857A>G	p.Asp286Gly	missense_variant	8/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.857A>G	p.Asp286Gly	missense_variant	8/27			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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 428682). This missense change has been observed in individual(s) with retinoblastoma (PMID: 23532519; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	May 20, 2024	Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PM2 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2015

​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;