chr13-48465334-C-T

Position:

• chr13-48465334-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000321.3(RB1):​c.2455C>T​(p.Leu819=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,609,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L819L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: RB1 NM_000321.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0920

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 13-48465334-C-T is Benign according to our data. Variant chr13-48465334-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 416487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48465334-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.092 with no splicing effect.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.2455C>T	p.Leu819=	synonymous_variant	23/27	ENST00000267163.6
RB1	NM_001407165.1	c.2455C>T	p.Leu819=	synonymous_variant	23/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.2455C>T	p.Leu819=	synonymous_variant	23/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.2455C>T	p.Leu819=	synonymous_variant	23/27
RB1	ENST00000643064.1	c.194+83891C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152104 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 251048 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000204 AC: 297 AN: 1457272 Hom.: 0 Cov.: 34 AF XY: 0.000181 AC XY: 131 AN XY: 725268

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000843

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152104 Hom.: 0 Cov.: 28 AF XY: 0.0000942 AC XY: 7 AN XY: 74296

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.0000982

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	RB1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2019	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 03, 2017	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. -

RB1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 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	-0.39
CADD	Benign	5.0
DANN	Benign	0.72

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: rs375751988; hg19: chr13-49039470;