13-48303700-C-A

Variant names:

• chr13-48303700-C-A
• rs1952048409
• ENST00000433480.4:n.24G>T

Variant summary

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

The ENST00000433480.4(RB1-DT):​n.24G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000885 in 565,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000088 (0 hom.)
• Consequence: RB1-DT ENST00000433480.4 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.01
• Publications: 0 publications found

Genes affected

RB1-DT (HGNC:42778): (RB1 divergent transcript)

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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• retinoblastoma

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

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

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=-0.22).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000433480.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1-DT	NR_046414.2		n.3G>T		non_coding_transcript_exon	Exon 1 of 3
	RB1	NM_000321.3	MANE Select	c.-213C>A		upstream_gene	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.-213C>A		upstream_gene	N/A	NP_001394094.1	A0A3B3IS71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1-DT	ENST00000433480.4	TSL:1	n.24G>T		non_coding_transcript_exon	Exon 1 of 3
	RB1-DT	ENST00000436963.3	TSL:3	n.21G>T		non_coding_transcript_exon	Exon 1 of 3
	RB1-DT	ENST00000700890.2		n.24G>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000885 AC: 5 AN: 565184 Hom.: 0 Cov.: 8 AF XY: 0.0000104 AC XY: 3 AN XY: 289450

African (AFR) AF: 0.00 AC: 0 AN: 10976

American (AMR) AF: 0.00 AC: 0 AN: 10404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13084

East Asian (EAS) AF: 0.00 AC: 0 AN: 24284

South Asian (SAS) AF: 0.00 AC: 0 AN: 43434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2102

European-Non Finnish (NFE) AF: 0.0000124 AC: 5 AN: 404112

Other (OTH) AF: 0.00 AC: 0 AN: 28678

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.96
PhyloP100		3.0
PromoterAI		0.27	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1952048409; hg19: chr13-48877836;