rs765386327

chr13-48464989-C-Achr13-48464989-C-Gchr13-48464989-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000321.3(RB1):c.2212-9C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 0)
  • Exomes 𝑓: 0.018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003631
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0290

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 13-48464989-C-A is Benign according to our data. Variant chr13-48464989-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 727657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.2212-9C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000267163.6
RB1	NM_001407165.1	c.2212-9C>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.2212-9C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000321.3	P1
RB1	ENST00000643064.1	c.194+83546C>A		intron_variant
RB1	ENST00000650461.1	c.2212-9C>A		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 25 AN: 54864 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.000198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000586

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00215

Gnomad SAS AF: 0.00424

Gnomad FIN AF: 0.000940

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000264

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0176 AC: 9129 AN: 520076 Hom.: 0 Cov.: 16 AF XY: 0.0157 AC XY: 4335 AN XY: 275530

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00473

Gnomad4 EAS exome AF: 0.00501

Gnomad4 SAS exome AF: 0.00404

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.0237

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000455 AC: 25 AN: 54892 Hom.: 0 Cov.: 0 AF XY: 0.000346 AC XY: 9 AN XY: 26030

Gnomad4 AFR AF: 0.000198

Gnomad4 AMR AF: 0.000586

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00215

Gnomad4 SAS AF: 0.00428

Gnomad4 FIN AF: 0.000940

Gnomad4 NFE AF: 0.000264

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Retinoblastoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

- -

RB1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	15
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.096
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs765386327; hg19: chr13-49039125;