13-48463741-G-A

Variant names:

• chr13-48463741-G-A
• rs121913295
• NM_000321.3:c.2117G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000321.3(RB1):​c.2117G>A​(p.Cys706Tyr) variant causes a missense change. 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.92
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• hereditary retinoblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 13-48463741-G-A is Pathogenic according to our data. Variant chr13-48463741-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2736033.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.2117G>A	p.Cys706Tyr	missense_variant	Exon 21 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2117G>A	p.Cys706Tyr	missense_variant	Exon 21 of 27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2117G>A	p.Cys706Tyr	missense_variant	Exon 21 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398612 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 699478

African (AFR) AF: 0.00 AC: 0 AN: 32072

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25758

East Asian (EAS) AF: 0.00 AC: 0 AN: 39194

South Asian (SAS) AF: 0.00 AC: 0 AN: 84862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5496

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1054986

Other (OTH) AF: 0.00 AC: 0 AN: 58298

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

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:2, UNILATERAL CASES:1, TOTAL CASES:3, PEDIGREES:3. ACMG Codes Applied:PM1, PM2, PM5, PS4SUP, PP3 -

Apr 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 706 of the RB1 protein (p.Cys706Tyr). This missense change has been observed in individual(s) with bilateral retinoblastoma and/or unilateral retinoblastoma (PMID: 8118465, 26084579, 30636860; Invitae). 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 expected to disrupt RB1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.
PhyloP100		5.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.2	D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0070	D;.
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.89		Gain of catalytic residue at S707 (P = 0);Gain of catalytic residue at S707 (P = 0);
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.98
gMVP		0.92
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs121913295; hg19: chr13-49037877;