rs143948310

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000321.3(RB1):c.1632A>G(p.Arg544=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,612,810 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 (★★).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

RB1
NM_000321.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.75

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 13-48381380-A-G is Benign according to our data. Variant chr13-48381380-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 416489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.75 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00221 (336/152368) while in subpopulation AFR AF= 0.00777 (323/41588). AF 95% confidence interval is 0.00707. There are 0 homozygotes in gnomad4. There are 167 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 336 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RB1	NM_000321.3 linkuse as main transcript	c.1632A>G	p.Arg544=	synonymous_variant	17/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1 linkuse as main transcript	c.1632A>G	p.Arg544=	synonymous_variant	17/27		NP_001394094.1
RB1	NM_001407166.1 linkuse as main transcript	c.1632A>G	p.Arg544=	synonymous_variant	17/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RB1	ENST00000267163.6 linkuse as main transcript	c.1632A>G	p.Arg544=	synonymous_variant	17/27	1	NM_000321.3	ENSP00000267163	P1
RB1	ENST00000650461.1 linkuse as main transcript	c.1632A>G	p.Arg544=	synonymous_variant	17/27			ENSP00000497193
RB1	ENST00000643064.1 linkuse as main transcript	c.132A>G	p.Arg44=	synonymous_variant	1/2			ENSP00000496005

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

336

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00779

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000536

AC:

134

AN:

250028

Hom.:

AF XY:

0.000415

AC XY:

AN XY:

135058

show subpopulations

Gnomad AFR exome

AF:

0.00757

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000208

AC:

304

AN:

1460442

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

726358

show subpopulations

Gnomad4 AFR exome

AF:

0.00754

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.00221

AC:

336

AN:

152368

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

167

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00777

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.00232

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 30, 2016	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

GeneDx

Mar 31, 2021

- -

RB1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2022

This variant is classified as 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

-0.52

CADD

Benign

DANN

Benign

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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