13-48381239-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000321.3(RB1):c.1499-8A>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002311
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0120

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 13-48381239-A-T is Benign according to our data. Variant chr13-48381239-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 458127.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 556 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.1499-8A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000267163.6
RB1	NM_001407165.1	c.1499-8A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RB1	NM_001407166.1	c.1499-8A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.1499-8A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000321.3	P1
RB1	ENST00000650461.1	c.1499-8A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RB1	ENST00000643064.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 16 AN: 150492 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000898

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000888

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00257 AC: 556 AN: 216410 Hom.: 0 AF XY: 0.00235 AC XY: 276 AN XY: 117352

Gnomad AFR exome AF: 0.00336

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00374

Gnomad EAS exome AF: 0.00155

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.00218

Gnomad NFE exome AF: 0.00323

Gnomad OTH exome AF: 0.00401

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000393 AC: 563 AN: 1431370 Hom.: 0 Cov.: 32 AF XY: 0.000367 AC XY: 261 AN XY: 710780

Gnomad4 AFR exome AF: 0.00171

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00116

Gnomad4 EAS exome AF: 0.000179

Gnomad4 SAS exome AF: 0.000546

Gnomad4 FIN exome AF: 0.0000953

Gnomad4 NFE exome AF: 0.000240

Gnomad4 OTH exome AF: 0.000918

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000106 AC: 16 AN: 150492 Hom.: 0 Cov.: 32 AF XY: 0.0000954 AC XY: 7 AN XY: 73362

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000898

Gnomad4 NFE AF: 0.0000888

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0215 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinoblastoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	6.2
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs1555286676; hg19: chr13-48955375;