NM_000321.3:c.2221C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4BP6BS2

The NM_000321.3(RB1):c.2221C>T(p.Arg741Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000207 in 967,298 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R741H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.83

Publications

3 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), Ambry Genetics, G2P
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 -4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 25 uncertain in NM_000321.3

BP4

Computational evidence support a benign effect (MetaRNN=0.31919622).

BP6

Variant 13-48465007-C-T is Benign according to our data. Variant chr13-48465007-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 527923.

BS2

High AC in GnomAdExome4 at 16 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.2221C>T	p.Arg741Cys	missense	Exon 22 of 27	NP_000312.2	P06400
	RB1	NM_001407165.1		c.2221C>T	p.Arg741Cys	missense	Exon 22 of 27	NP_001394094.1	A0A3B3IS71

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RB1	ENST00000267163.6	TSL:1 MANE Select	c.2221C>T	p.Arg741Cys	missense	Exon 22 of 27	ENSP00000267163.4	P06400
RB1	ENST00000467505.6	TSL:1	n.*1589C>T		non_coding_transcript_exon	Exon 17 of 22	ENSP00000434702.1	Q92728
RB1	ENST00000467505.6	TSL:1	n.*1589C>T		3_prime_UTR	Exon 17 of 22	ENSP00000434702.1	Q92728

Frequencies

GnomAD3 genomes

AF:

0.0000360

AC:

AN:

111194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000643

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000349

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000163

AC:

AN:

245580

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.0000555

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000187

AC:

AN:

856104

Hom.:

Cov.:

AF XY:

0.0000227

AC XY:

AN XY:

440210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24560

American (AMR)

AF:

0.00

AC:

AN:

38166

Ashkenazi Jewish (ASJ)

AF:

0.000119

AC:

AN:

16780

East Asian (EAS)

AF:

0.0000414

AC:

AN:

24132

South Asian (SAS)

AF:

0.0000277

AC:

AN:

72132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40908

Middle Eastern (MID)

AF:

0.000385

AC:

AN:

2600

European-Non Finnish (NFE)

AF:

0.0000166

AC:

AN:

601710

Other (OTH)

AF:

0.00

AC:

AN:

35116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.0000360

AC:

AN:

111194

Hom.:

Cov.:

AF XY:

0.0000396

AC XY:

AN XY:

50510

show subpopulations

African (AFR)

AF:

0.0000643

AC:

AN:

31116

American (AMR)

AF:

0.00

AC:

AN:

7780

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3140

East Asian (EAS)

AF:

0.00

AC:

AN:

3374

South Asian (SAS)

AF:

0.00

AC:

AN:

3304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

100

European-Non Finnish (NFE)

AF:

0.0000349

AC:

AN:

57266

Other (OTH)

AF:

0.00

AC:

AN:

1452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.0000403

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinoblastoma (2)

Hereditary cancer-predisposing syndrome (1)

Malignant tumor of urinary bladder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

Eigen

Benign

-0.053

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.071

MetaRNN

Benign

0.32

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

0.26

PhyloP100

3.8

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.40

Sift

Benign

0.077

Sift4G

Benign

0.15

Polyphen

0.23

Vest4

0.37

MutPred

0.54

Gain of sheet (P = 0.0101)

MVP

0.84

MPC

0.62

ClinPred

0.36

GERP RS

4.6

Varity_R

0.45

gMVP

0.56

Mutation Taster

=57/43

polymorphism

(source)

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

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