13-48380039-A-T

Variant names:

• chr13-48380039-A-T
• rs9535023
• NM_000321.3:c.1390-14A>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000321.3(RB1):​c.1390-14A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 1,242,656 control chromosomes in the GnomAD database, including 2,392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (221 hom., cov: 29)
  • Exomes 𝑓: 0.056 (2171 hom.)
• Consequence: RB1 NM_000321.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.649

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]

LOC112268118 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-48380039-A-T is Benign according to our data. Variant chr13-48380039-A-T is described in ClinVar as [Benign]. Clinvar id is 167566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1390-14A>T		intron_variant	Intron 14 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1390-14A>T		intron_variant	Intron 14 of 26		NP_001394094.1
RB1	NM_001407166.1	c.1390-14A>T		intron_variant	Intron 14 of 16		NP_001394095.1
LOC112268118	XR_002957522.2	n.-165T>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1390-14A>T		intron_variant	Intron 14 of 26	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1390-14A>T		intron_variant	Intron 14 of 26			ENSP00000497193.1

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 6973 AN: 148040 Hom.: 221 Cov.: 29

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0927

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000588

Gnomad SAS AF: 0.00909

Gnomad FIN AF: 0.0448

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0753

Gnomad OTH AF: 0.0541

GnomAD3 exomes AF: 0.0417 AC: 4720 AN: 113174 Hom.: 154 AF XY: 0.0410 AC XY: 2607 AN XY: 63566

Gnomad AFR exome AF: 0.00792

Gnomad AMR exome AF: 0.0260

Gnomad ASJ exome AF: 0.0322

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0127

Gnomad FIN exome AF: 0.0573

Gnomad NFE exome AF: 0.0640

Gnomad OTH exome AF: 0.0426

GnomAD4 exome AF: 0.0556 AC: 60894 AN: 1094532 Hom.: 2171 Cov.: 19 AF XY: 0.0549 AC XY: 30092 AN XY: 547818

Gnomad4 AFR exome AF: 0.00764

Gnomad4 AMR exome AF: 0.0306

Gnomad4 ASJ exome AF: 0.0351

Gnomad4 EAS exome AF: 0.0000683

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.0529

Gnomad4 NFE exome AF: 0.0639

Gnomad4 OTH exome AF: 0.0483

GnomAD4 genome AF: 0.0470 AC: 6969 AN: 148124 Hom.: 221 Cov.: 29 AF XY: 0.0449 AC XY: 3238 AN XY: 72146

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.0457

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.000589

Gnomad4 SAS AF: 0.00869

Gnomad4 FIN AF: 0.0448

Gnomad4 NFE AF: 0.0753

Gnomad4 OTH AF: 0.0536

Alfa AF: 0.0568 Hom.: 38

Bravo AF: 0.0471

Asia WGS AF: 0.0240 AC: 85 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 13, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 24, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RB1 c.1390-14A>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 1084/24708 control chromosomes (28 homozygotes) at a frequency of 0.0438724, which is approximately 1053 times the estimated maximal expected allele frequency of a pathogenic RB1 variant (0.0000417), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. -

Hereditary cancer-predisposing syndrome Benign:1

Dec 09, 2019

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.2
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs9535023; hg19: chr13-48954175; COSMIC: COSV57303499; COSMIC: COSV57303499;