rs387906521

chr13-48303715-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The ENST00000700890.1(RB1-DT):n.6C>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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1-DT ENST00000700890.1 non_coding_transcript_exon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.76

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• 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]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3			upstream_gene_variant		ENST00000267163.6
RB1-DT	NR_046414.2			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6			upstream_gene_variant		1	NM_000321.3	P1

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

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: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects RB1 function (PMID: 1881452). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 13086). This variant has been observed in individual(s) with retinoblastoma (PMID: 1881452, 10673998, 20447117). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant occurs in a non-coding region of the RB1 gene. It does not change the encoded amino acid sequence of the RB1 protein. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 05, 1991	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2019

The c.-198G>A pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the RB1 gene. This pathogenic mutation results from a G to A substitution 198 bases upstream from the first translated codon. 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. Of note, multiple unaffected individuals were determined to carry the alteration, suggesting reduced penetrance (Sakai T et al. Nature. 1991;353(6339):83-6). This mutation has also been described in a patient presenting with unilateral retinoblastoma at 18 months of age, who had no family history of retinoblastoma (Pradhan MA et al. Clin. Experiment. Ophthalmol. 2010;38(3):231-6) and as a de novo alteration in a male individual presenting with unilateral retinoblastoma at 15 months of age ( Zajaczek S, et al. Eur. J. Cancer 1998 Nov; 34(12):1919-21). Based on nucleotide sequence alignment, this position is highly conserved in vertebrate species. Based on the supporting evidence, c.-198G>A is interpreted as a disease-causing mutation exhibiting reduced penetrance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Uncertain	0.98

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906521; hg19: chr13-48877851;