Genetic Variant NM_000321.3:c.380+45C>T (chr13-48342759-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000321.3(RB1):c.380+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,330,802 control chromosomes in the GnomAD database, including 39,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3605 hom., cov: 32)

Exomes 𝑓: 0.24 ( 35859 hom. )

Consequence

RB1
NM_000321.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.96

Publications

17 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 13-48342759-C-T is Benign according to our data. Variant chr13-48342759-C-T is described in ClinVar as Benign. ClinVar VariationId is 255824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
RB1	NM_000321.3	MANE Select	c.380+45C>T	intron	N/A	NP_000312.2	P06400
RB1	NM_001407165.1		c.380+45C>T	intron	N/A	NP_001394094.1	A0A3B3IS71
RB1	NM_001407166.1		c.380+45C>T	intron	N/A	NP_001394095.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RB1	ENST00000267163.6	TSL:1 MANE Select	c.380+45C>T	intron	N/A	ENSP00000267163.4	P06400
RB1	ENST00000467505.6	TSL:1	n.138-17258C>T	intron	N/A	ENSP00000434702.1	Q92728
RB1	ENST00000924352.1		c.380+45C>T	intron	N/A	ENSP00000594411.1

Frequencies

GnomAD3 genomes

AF:

0.214

AC:

32434

AN:

151694

Hom.:

3610

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.342

Gnomad AMR

AF:

0.187

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.227

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.247

Gnomad OTH

AF:

0.207

GnomAD2 exomes

AF:

0.236

AC:

56447

AN:

238912

AF XY:

0.237

show subpopulations

Gnomad AFR exome

AF:

0.150

Gnomad AMR exome

AF:

0.201

Gnomad ASJ exome

AF:

0.198

Gnomad EAS exome

AF:

0.237

Gnomad FIN exome

AF:

0.262

Gnomad NFE exome

AF:

0.254

Gnomad OTH exome

AF:

0.233

GnomAD4 exome

AF:

0.244

AC:

287744

AN:

1178990

Hom.:

35859

Cov.:

AF XY:

0.243

AC XY:

145832

AN XY:

599146

show subpopulations

African (AFR)

AF:

0.149

AC:

4089

AN:

27518

American (AMR)

AF:

0.199

AC:

8542

AN:

42898

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

4686

AN:

24124

East Asian (EAS)

AF:

0.241

AC:

9202

AN:

38192

South Asian (SAS)

AF:

0.243

AC:

19147

AN:

78666

European-Finnish (FIN)

AF:

0.262

AC:

13563

AN:

51764

Middle Eastern (MID)

AF:

0.155

AC:

779

AN:

5012

European-Non Finnish (NFE)

AF:

0.251

AC:

215755

AN:

859840

Other (OTH)

AF:

0.235

AC:

11981

AN:

50976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

10532

21063

31595

42126

52658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6546

13092

19638

26184

32730

<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:

0.214

AC:

32432

AN:

151812

Hom.:

3605

Cov.:

AF XY:

0.216

AC XY:

16013

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.151

AC:

6251

AN:

41468

American (AMR)

AF:

0.187

AC:

2850

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

693

AN:

3466

East Asian (EAS)

AF:

0.227

AC:

1176

AN:

5182

South Asian (SAS)

AF:

0.243

AC:

1169

AN:

4810

European-Finnish (FIN)

AF:

0.262

AC:

2764

AN:

10538

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.247

AC:

16744

AN:

67778

Other (OTH)

AF:

0.204

AC:

430

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1312

2624

3937

5249

6561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

358

716

1074

1432

1790

<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:

0.183

Hom.:

662

Bravo

AF:

0.207

Asia WGS

AF:

0.229

AC:

794

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.070

(source)

DANN

Benign

0.33

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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