Genetic Variant NM_000321.3:c.2664-10T>A (chr13-48477345-T-A) – 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.2664-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,598,702 control chromosomes in the GnomAD database, including 49,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3473 hom., cov: 33)

Exomes 𝑓: 0.25 ( 46321 hom. )

Consequence

RB1
NM_000321.3 intron

Scores

Splicing: ADA: 0.0005315

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.676

Publications

29 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=-0.86).

BP6

Variant 13-48477345-T-A is Benign according to our data. Variant chr13-48477345-T-A is described in ClinVar as Benign. ClinVar VariationId is 92843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.252 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.2664-10T>A	intron	N/A	NP_000312.2	P06400
RB1	NM_001407165.1		c.2664-10T>A	intron	N/A	NP_001394094.1	A0A3B3IS71
RB1	NM_001407168.1		c.114-10T>A	intron	N/A	NP_001394097.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RB1	ENST00000267163.6	TSL:1 MANE Select	c.2664-10T>A	intron	N/A	ENSP00000267163.4	P06400
RB1	ENST00000467505.6	TSL:1	n.*2032-10T>A	intron	N/A	ENSP00000434702.1	Q92728
RB1	ENST00000484879.1	TSL:1	n.398-10T>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30705

AN:

152034

Hom.:

3477

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0960

Gnomad AMI

AF:

0.344

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.202

Gnomad EAS

AF:

0.229

Gnomad SAS

AF:

0.264

Gnomad FIN

AF:

0.267

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.253

Gnomad OTH

AF:

0.194

GnomAD2 exomes

AF:

0.237

AC:

58755

AN:

247544

AF XY:

0.241

show subpopulations

Gnomad AFR exome

AF:

0.0925

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.197

Gnomad EAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.266

Gnomad NFE exome

AF:

0.259

Gnomad OTH exome

AF:

0.235

GnomAD4 exome

AF:

0.249

AC:

360651

AN:

1446550

Hom.:

46321

Cov.:

AF XY:

0.250

AC XY:

179672

AN XY:

720096

show subpopulations

African (AFR)

AF:

0.0871

AC:

2892

AN:

33186

American (AMR)

AF:

0.197

AC:

8743

AN:

44342

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

5052

AN:

25984

East Asian (EAS)

AF:

0.242

AC:

9554

AN:

39460

South Asian (SAS)

AF:

0.265

AC:

22608

AN:

85404

European-Finnish (FIN)

AF:

0.268

AC:

14273

AN:

53216

Middle Eastern (MID)

AF:

0.151

AC:

860

AN:

5684

European-Non Finnish (NFE)

AF:

0.257

AC:

282472

AN:

1099416

Other (OTH)

AF:

0.237

AC:

14197

AN:

59858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

11971

23941

35912

47882

59853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9496

18992

28488

37984

47480

<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:

0.202

AC:

30698

AN:

152152

Hom.:

3473

Cov.:

AF XY:

0.205

AC XY:

15222

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0957

AC:

3976

AN:

41552

American (AMR)

AF:

0.181

AC:

2757

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

700

AN:

3466

East Asian (EAS)

AF:

0.229

AC:

1185

AN:

5180

South Asian (SAS)

AF:

0.264

AC:

1275

AN:

4826

European-Finnish (FIN)

AF:

0.267

AC:

2820

AN:

10566

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.253

AC:

17225

AN:

67974

Other (OTH)

AF:

0.191

AC:

403

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1226

2452

3678

4904

6130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.225

Hom.:

735

Bravo

AF:

0.192

Asia WGS

AF:

0.233

AC:

806

AN:

3464

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinoblastoma (6)

not specified (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.015

(source)

DANN

Benign

0.21

PhyloP100

-0.68

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00053

dbscSNV1_RF

Benign

0.062

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