chr13-48381254-A-G

Position:

• chr13-48381254-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000321.3(RB1):​c.1506A>G​(p.Thr502=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.346

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 13-48381254-A-G is Benign according to our data. Variant chr13-48381254-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410931.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1506A>G	p.Thr502=	synonymous_variant	17/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1506A>G	p.Thr502=	synonymous_variant	17/27		NP_001394094.1
RB1	NM_001407166.1	c.1506A>G	p.Thr502=	synonymous_variant	17/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1506A>G	p.Thr502=	synonymous_variant	17/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1	c.1506A>G	p.Thr502=	synonymous_variant	17/27			ENSP00000497193
RB1	ENST00000643064.1	c.6A>G	p.Thr2=	synonymous_variant	1/2			ENSP00000496005

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455580 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinoblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2017

This sequence change affects codon 502 of the RB1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RB1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RB1-related disease. ClinVar contains an entry for this variant (Variation ID: 410931). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.1
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060503081; hg19: chr13-48955390;