rs3092895

chr13-48453004-A-Gchr13-48453004-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000321.3(RB1):c.1707A>G(p.Leu569=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,612,770 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (5 hom.)
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.779

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 13-48453004-A-G is Benign according to our data. Variant chr13-48453004-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 312291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48453004-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.779 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000552 (84/152268) while in subpopulation SAS AF= 0.00166 (8/4824). AF 95% confidence interval is 0.000825. There are 1 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.1707A>G	p.Leu569=	synonymous_variant	18/27	ENST00000267163.6
RB1	NM_001407165.1	c.1707A>G	p.Leu569=	synonymous_variant	18/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.1707A>G	p.Leu569=	synonymous_variant	18/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.1707A>G	p.Leu569=	synonymous_variant	18/27
RB1	ENST00000643064.1	c.194+71561A>G		intron_variant
RB1	ENST00000480491.1	n.406A>G		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000638 AC: 160 AN: 250660 Hom.: 0 AF XY: 0.000671 AC XY: 91 AN XY: 135542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.000756

Gnomad NFE exome AF: 0.000775

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000540 AC: 788 AN: 1460502 Hom.: 5 Cov.: 31 AF XY: 0.000612 AC XY: 445 AN XY: 726594

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00224

Gnomad4 FIN exome AF: 0.000967

Gnomad4 NFE exome AF: 0.000444

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.000332

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.000818

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Benign:4

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 29, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 15, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 24, 2015	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

RB1: BP4, BP7, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	9.6
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3092895; hg19: chr13-49027140;