rs387906521

Variant names:

• chr13-48303715-G-A
• rs387906521
• ENST00000433480.4:n.9C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BP4

The ENST00000433480.4(RB1-DT):​n.9C>T variant causes a non coding transcript exon 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 (★★). ClinVar reports functional evidence for this variant: "SCV001580876: Experimental studies have shown that this variant affects RB1 function (PMID:1881452)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1-DT ENST00000433480.4 non_coding_transcript_exon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.76
• Publications: 6 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), Ambry Genetics, G2P
• 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 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001580876: Experimental studies have shown that this variant affects RB1 function (PMID: 1881452).; SCV000580798: In one study, c.-198G>A was determined to segregate with disease in a family with hereditary retinoblastoma. In addition, these authors demonstrated that the alteration interfered with binding of an essential RB1 transcription factor. Sakai T et al. Nature. 1991;353(6339):83-6).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48303715-G-A is Pathogenic according to our data. Variant chr13-48303715-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22). . Strength limited to SUPPORTING due to the PP5.

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	NM_000321.3	MANE Select	c.-198G>A		upstream_gene	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.-198G>A		upstream_gene	N/A	NP_001394094.1	A0A3B3IS71
	RB1	NM_001407166.1		c.-198G>A		upstream_gene	N/A	NP_001394095.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1-DT	ENST00000433480.4	TSL:1	n.9C>T		non_coding_transcript_exon	Exon 1 of 3
	RB1-DT	ENST00000436963.3	TSL:3	n.6C>T		non_coding_transcript_exon	Exon 1 of 3
	RB1-DT	ENST00000700890.2		n.9C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 665436 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 336352

African (AFR) AF: 0.00 AC: 0 AN: 12902

American (AMR) AF: 0.00 AC: 0 AN: 10760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14006

East Asian (EAS) AF: 0.00 AC: 0 AN: 24752

South Asian (SAS) AF: 0.00 AC: 0 AN: 45746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2320

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 494398

Other (OTH) AF: 0.00 AC: 0 AN: 31984

GnomAD4 genome Cov.: 32

Alfa AF: 0.00126 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Retinoblastoma (4)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
PhyloP100		3.8
PromoterAI		-0.90	Under-expression

Splicing

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

Other links and lift over

dbSNP: rs387906521; hg19: chr13-48877851;