dbSNP rs185587: RB1:c.1128-72G>A (chr13-48373333-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000321.3(RB1):c.1128-72G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00733 in 931,958 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0056 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0077 ( 44 hom. )

Consequence

RB1
NM_000321.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.405

Publications

7 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: Labcorp Genetics (formerly Invitae), Orphanet, 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 -12 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00556 (846/152188) while in subpopulation NFE AF = 0.00865 (588/67956). AF 95% confidence interval is 0.00807. There are 5 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 846 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.1128-72G>A	intron_variant	Intron 11 of 26	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.1128-72G>A	intron_variant	Intron 11 of 26		NP_001394094.1
RB1	NM_001407166.1 link	c.1128-72G>A	intron_variant	Intron 11 of 16		NP_001394095.1
LOC112268118	XR_002957522.2 link	n.121+827C>T	intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.1128-72G>A		intron_variant	Intron 11 of 26	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

AF:

0.00556

AC:

846

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00583

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00528

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00865

Gnomad OTH

AF:

0.00669

GnomAD4 exome

AF:

0.00768

AC:

5987

AN:

779770

Hom.:

AF XY:

0.00758

AC XY:

3140

AN XY:

414068

show subpopulations

African (AFR)

AF:

0.00189

AC:

AN:

20062

American (AMR)

AF:

0.00594

AC:

249

AN:

41922

Ashkenazi Jewish (ASJ)

AF:

0.00497

AC:

107

AN:

21548

East Asian (EAS)

AF:

0.00

AC:

AN:

36024

South Asian (SAS)

AF:

0.00311

AC:

215

AN:

69026

European-Finnish (FIN)

AF:

0.00805

AC:

421

AN:

52326

Middle Eastern (MID)

AF:

0.0134

AC:

AN:

3870

European-Non Finnish (NFE)

AF:

0.00932

AC:

4636

AN:

497236

Other (OTH)

AF:

0.00712

AC:

269

AN:

37756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

290

580

870

1160

1450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.00556

AC:

846

AN:

152188

Hom.:

Cov.:

AF XY:

0.00546

AC XY:

406

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41532

American (AMR)

AF:

0.00582

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00269

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00528

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00865

AC:

588

AN:

67956

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00658

Hom.:

3268

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.6

(source)

DANN

Benign

0.53

PhyloP100

0.41

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over