13-48381322-C-G

Position:

• chr13-48381322-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000321.3(RB1):​c.1574C>G​(p.Ala525Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,611,652 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A525T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0058 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (7 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 7.57

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011211336).
• BP6: Variant 13-48381322-C-G is Benign according to our data. Variant chr13-48381322-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 135118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00577 (876/151926) while in subpopulation AFR AF= 0.0202 (836/41440). AF 95% confidence interval is 0.019. There are 11 homozygotes in gnomad4. There are 387 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 876 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1	NM_000321.3	c.1574C>G	p.Ala525Gly	missense_variant	17/27	ENST00000267163.6
RB1	NM_001407165.1	c.1574C>G	p.Ala525Gly	missense_variant	17/27
RB1	NM_001407166.1	c.1574C>G	p.Ala525Gly	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1	ENST00000267163.6	c.1574C>G	p.Ala525Gly	missense_variant	17/27	1	NM_000321.3	P1
RB1	ENST00000650461.1	c.1574C>G	p.Ala525Gly	missense_variant	17/27
RB1	ENST00000643064.1	c.74C>G	p.Ala25Gly	missense_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 875 AN: 151808 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00153 AC: 381 AN: 249146 Hom.: 5 AF XY: 0.00110 AC XY: 148 AN XY: 134600

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.000824

GnomAD4 exome AF: 0.000619 AC: 903 AN: 1459726 Hom.: 7 Cov.: 32 AF XY: 0.000551 AC XY: 400 AN XY: 726022

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.00162

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00577 AC: 876 AN: 151926 Hom.: 11 Cov.: 32 AF XY: 0.00521 AC XY: 387 AN XY: 74214

Gnomad4 AFR AF: 0.0202

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00103 Hom.: 1

Bravo AF: 0.00687

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00187 AC: 227

Asia WGS AF: 0.00145 AC: 5 AN: 3470

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	May 20, 2024	Case and Pedigree Information: BILATERAL CASES:0, UNILATERAL CASES:1, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:BS1, BS2 -
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	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 12, 2018	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 14, 2015	This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2020

This variant is associated with the following publications: (PMID: 22995991, 20981092, 24728327, 12541220, 27884173, 27153395, 26332594) -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Pathogenic	0.76
Sift	Benign	0.099	T;.
Sift4G	Uncertain	0.028	D;.
Polyphen		1.0	D;.
Vest4		0.90
MVP		0.80
MPC		0.90
ClinPred		0.025	T
GERP RS		5.2
Varity_R		0.74
gMVP		0.51

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: rs4151539; hg19: chr13-48955458; COSMIC: COSV57300274;