rs587778640

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6BS2_Supporting

The NM_000321.3(RB1):c.1573G>A(p.Ala525Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,611,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A525G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:3O:1

Conservation

PhyloP100: 7.72

Publications

6 publications found

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 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 13-48381321-G-A is Benign according to our data. Variant chr13-48381321-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135119.

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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	UniProt
RB1	NM_000321.3	MANE Select	c.1573G>A	p.Ala525Thr	missense	Exon 17 of 27	NP_000312.2	P06400
RB1	NM_001407165.1		c.1573G>A	p.Ala525Thr	missense	Exon 17 of 27	NP_001394094.1	A0A3B3IS71
RB1	NM_001407166.1		c.1573G>A	p.Ala525Thr	missense	Exon 17 of 17	NP_001394095.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RB1	ENST00000267163.6	TSL:1 MANE Select	c.1573G>A	p.Ala525Thr	missense	Exon 17 of 27	ENSP00000267163.4	P06400
RB1	ENST00000467505.6	TSL:1	n.*941G>A		non_coding_transcript_exon	Exon 12 of 22	ENSP00000434702.1	Q92728
RB1	ENST00000467505.6	TSL:1	n.*941G>A		3_prime_UTR	Exon 12 of 22	ENSP00000434702.1	Q92728

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000602

AC:

AN:

249180

AF XY:

0.0000817

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1459934

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33380

American (AMR)

AF:

0.00

AC:

AN:

44494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.000152

AC:

AN:

39504

South Asian (SAS)

AF:

0.000198

AC:

AN:

85806

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1111246

Other (OTH)

AF:

0.0000332

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151946

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41364

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67972

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3470

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinoblastoma (3)

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Ovarian cancer (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.69

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.6

PhyloP100

7.7

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.86

Sift

Benign

0.033

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.89

MutPred

0.72

Gain of catalytic residue at K524 (P = 5e-04)

MVP

0.91

MPC

1.1

ClinPred

0.26

GERP RS

5.3

PromoterAI

-0.0045

Neutral

(source)

Varity_R

0.93

gMVP

0.65

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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