rs200844292

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000321.3(RB1):c.929G>A(p.Gly310Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000376 in 1,570,788 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 3.53

Publications

18 publications found

Variant links:

COSMIC-nc: COSV57300055

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 Gene-Disease associations (from GenCC):

hereditary retinoblastoma
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
retinoblastoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
melanoma
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

RB1 links:

LOC112268118 (HGNC:):

LOC112268118 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07991445).

BP6

Variant 13-48364961-G-A is Benign according to our data. Variant chr13-48364961-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 237678.

BS2

High AC in GnomAd4 at 42 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RB1	NM_000321.3	MANE Select	c.929G>A	p.Gly310Glu	missense	Exon 9 of 27	NP_000312.2
RB1	NM_001407165.1		c.929G>A	p.Gly310Glu	missense	Exon 9 of 27	NP_001394094.1
RB1	NM_001407166.1		c.929G>A	p.Gly310Glu	missense	Exon 9 of 17	NP_001394095.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RB1	ENST00000267163.6	TSL:1 MANE Select	c.929G>A	p.Gly310Glu	missense	Exon 9 of 27	ENSP00000267163.4
RB1	ENST00000467505.6	TSL:1	n.*297G>A		non_coding_transcript_exon	Exon 4 of 22	ENSP00000434702.1
RB1	ENST00000467505.6	TSL:1	n.*297G>A		3_prime_UTR	Exon 4 of 22	ENSP00000434702.1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

151918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000280

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000366

AC:

AN:

196856

AF XY:

0.000388

show subpopulations

Gnomad AFR exome

AF:

0.0000903

Gnomad AMR exome

AF:

0.000987

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000104

Gnomad NFE exome

AF:

0.000402

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.000387

AC:

549

AN:

1418752

Hom.:

Cov.:

AF XY:

0.000383

AC XY:

269

AN XY:

702480

show subpopulations

African (AFR)

AF:

0.0000939

AC:

AN:

31956

American (AMR)

AF:

0.000999

AC:

AN:

42048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25312

East Asian (EAS)

AF:

0.00

AC:

AN:

37588

South Asian (SAS)

AF:

0.00

AC:

AN:

81570

European-Finnish (FIN)

AF:

0.000178

AC:

AN:

50588

Middle Eastern (MID)

AF:

0.000560

AC:

AN:

5360

European-Non Finnish (NFE)

AF:

0.000434

AC:

471

AN:

1086058

Other (OTH)

AF:

0.000360

AC:

AN:

58272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000276

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41476

American (AMR)

AF:

0.00131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.0000947

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000280

AC:

AN:

67966

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000477

Hom.:

Bravo

AF:

0.000363

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000236

AC:

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3470

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinoblastoma (6)

not provided (3)

not specified (3)

Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.81

M_CAP

Benign

0.059

MetaRNN

Benign

0.080

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

2.0

PhyloP100

3.5

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.74

Sift

Benign

0.19

Sift4G

Benign

0.094

Polyphen

1.0

Vest4

0.82

MVP

0.89

MPC

0.61

ClinPred

0.062

GERP RS

4.7

Varity_R

0.39

gMVP

0.67

Mutation Taster

=37/63

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over