rs387906521

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. 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 (★★).

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

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

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-48303715-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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.-198G>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.-198G>A		upstream_gene_variant		1	NM_000321.3	ENSP00000267163.4

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

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:4

Sep 05, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 20, 2024

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PS3, PM2, PS4SUP, PP5 -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 13086). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects RB1 function (PMID: 1881452). For these reasons, this variant has been classified as Pathogenic. 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 occurs in a non-coding region of the RB1 gene. It does not change the encoded amino acid sequence of the RB1 protein. This variant is not present in population databases (gnomAD no frequency). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 24, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;