13-48303724-G-T

Variant names:

• chr13-48303724-G-T
• rs387906520
• NM_000321.3:c.-189G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000321.3(RB1):​c.-189G>T variant causes a upstream gene change. 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 upstream_gene
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.76
• Publications: 4 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48303724-G-T is Pathogenic according to our data. Variant chr13-48303724-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 13085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. 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	NM_000321.3	MANE Select	c.-189G>T		upstream_gene	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.-189G>T		upstream_gene	N/A	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.-189G>T		upstream_gene	N/A	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.-189G>T		upstream_gene	N/A	ENSP00000267163.4	P06400
	RB1-DT	ENST00000433480.4	TSL:1	n.-1C>A		upstream_gene	N/A
	RB1	ENST00000467505.6	TSL:1	n.-189G>T		upstream_gene	N/A	ENSP00000434702.1	Q92728

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 780024 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 390146

African (AFR) AF: 0.00 AC: 0 AN: 15096

American (AMR) AF: 0.00 AC: 0 AN: 12014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14948

East Asian (EAS) AF: 0.00 AC: 0 AN: 25312

South Asian (SAS) AF: 0.00 AC: 0 AN: 49094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2584

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 596266

Other (OTH) AF: 0.00 AC: 0 AN: 35820

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Retinoblastoma (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		3.8
PromoterAI		-0.89	Under-expression

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387906520;

hg19: chr13-48877860;