chr13-48303747-G-A

Variant names:

• chr13-48303747-G-A
• rs1299286582
• ENST00000650461.1:c.-166G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000650461.1(RB1):​c.-166G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 953,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: RB1 ENST00000650461.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.626
• Publications: 0 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-DT (HGNC:42778): (RB1 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.-166G>A		upstream_gene_variant		ENST00000267163.6	NP_000312.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.-166G>A		upstream_gene_variant		1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 953218 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 471996

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000540 AC: 1 AN: 18520

American (AMR) AF: 0.00 AC: 0 AN: 14006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16992

East Asian (EAS) AF: 0.00 AC: 0 AN: 26224

South Asian (SAS) AF: 0.00 AC: 0 AN: 55560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3004

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 747126

Other (OTH) AF: 0.00 AC: 0 AN: 41754

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	0.97
PhyloP100		0.63
PromoterAI		-0.049	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1299286582; hg19: chr13-48877883;