Genetic Variant RB1:c.1499-8A>T (chr13-48381239-A-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_000321.3(RB1):c.1499-8A>T variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.00002311

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0120

Variant links:

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]

RB1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.1499-8A>T	splice_region_variant, intron_variant	Intron 16 of 26	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.1499-8A>T	splice_region_variant, intron_variant	Intron 16 of 26		NP_001394094.1
RB1	NM_001407166.1 link	c.1499-8A>T	splice_region_variant, intron_variant	Intron 16 of 16		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RB1	ENST00000267163.6 link	c.1499-8A>T	splice_region_variant, intron_variant	Intron 16 of 26	1	NM_000321.3	ENSP00000267163.4	P06400
RB1	ENST00000650461.1 link	c.1499-8A>T	splice_region_variant, intron_variant	Intron 16 of 26			ENSP00000497193.1	A0A3B3IS71
RB1	ENST00000643064.1 link	c.-13A>T	upstream_gene_variant				ENSP00000496005.1	A0A2R8Y743

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150492

Hom.:

Cov.:

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.:

AF XY:

0.00235

AC XY:

276

AN XY:

117352

show subpopulations

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.:

Cov.:

AF XY:

0.000367

AC XY:

261

AN XY:

710780

show subpopulations

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:

AN:

150492

Hom.:

Cov.:

AF XY:

0.0000954

AC XY:

AN XY:

73362

show subpopulations

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.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Retinoblastoma

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over