dbSNP rs4151510: RB1:c.1128-2366G>A (chr13-48371039-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000321.3(RB1):c.1128-2366G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 152,236 control chromosomes in the GnomAD database, including 1,027 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 0.11 ( 1027 hom., cov: 32)

Consequence

RB1
NM_000321.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.63

Publications

11 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=-0.93).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.1128-2366G>A	intron_variant	Intron 11 of 26	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.1128-2366G>A	intron_variant	Intron 11 of 26		NP_001394094.1
RB1	NM_001407166.1 link	c.1128-2366G>A	intron_variant	Intron 11 of 16		NP_001394095.1
LOC112268118	XR_002957522.2 link	n.121+3121C>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.1128-2366G>A		intron_variant	Intron 11 of 26	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

AF:

0.109

AC:

16516

AN:

152118

Hom.:

1029

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0484

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.167

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0868

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.128

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.112

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.108

AC:

16512

AN:

152236

Hom.:

1027

Cov.:

AF XY:

0.111

AC XY:

8238

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0483

AC:

2006

AN:

41556

American (AMR)

AF:

0.167

AC:

2555

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

369

AN:

3472

East Asian (EAS)

AF:

0.0868

AC:

450

AN:

5186

South Asian (SAS)

AF:

0.117

AC:

564

AN:

4832

European-Finnish (FIN)

AF:

0.128

AC:

1353

AN:

10588

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.130

AC:

8863

AN:

68004

Other (OTH)

AF:

0.110

AC:

233

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

763

1526

2288

3051

3814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<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:

0.123

Hom.:

1627

Bravo

AF:

0.108

Asia WGS

AF:

0.0880

AC:

307

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.050

(source)

DANN

Benign

0.58

PhyloP100

-2.6

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over