rs1131690851

Positions:

• chr13-48379606-G-A
• chr13-48379606-G-C
• chr13-48379606-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000321.3(RB1):​c.1345G>A​(p.Gly449Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G449E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.09

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 16 ACMG points.

• PM1: In a helix (size 29) in uniprot entity RB_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-48379607-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2736027.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 13-48379606-G-A is Pathogenic according to our data. Variant chr13-48379606-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.1345G>A	p.Gly449Arg	missense_variant	14/27	ENST00000267163.6
LOC112268118	XR_002957522.2	n.40+229C>T		intron_variant, non_coding_transcript_variant
RB1	NM_001407165.1	c.1345G>A	p.Gly449Arg	missense_variant	14/27
RB1	NM_001407166.1	c.1345G>A	p.Gly449Arg	missense_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.1345G>A	p.Gly449Arg	missense_variant	14/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.1345G>A	p.Gly449Arg	missense_variant	14/27

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

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	Invitae	Feb 17, 2020	For these reasons, this variant has been classified as Pathogenic. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to be de novo in individuals affected with bilateral retinoblastoma (PMID: 28193182, Invitae) and has been observed to segregate with retinoblastoma in a family (PMID: 17096365). The variant is also known as g.76442G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 428669). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 449 of the RB1 protein (p.Gly449Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -
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:PM1, PM2 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2012

Co-segregation data for this variant is currently unavailable. This variant has not been detected in conjunction with a pathogenic mutation to date. Allele frequency data in population-based cohorts is not currently available. This amino acid position is completely conserved on sequence alignment.This alteration is predicted to be deleterious with a score of 0.010 (conservation: 1.79) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.4	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.80		Gain of catalytic residue at Q444 (P = 0);Gain of catalytic residue at Q444 (P = 0);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.39		Position offset: -12

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131690851; hg19: chr13-48953742; COSMIC: COSV104565163; COSMIC: COSV104565163;