rs139743319

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002894.3(RBBP8):c.1367A>G(p.His456Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,614,200 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 5 hom. )

Consequence

RBBP8
NM_002894.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.18

Publications

7 publications found

Variant links:

Genes affected

RBBP8 (HGNC:9891): (RB binding protein 8, endonuclease) The protein encoded by this gene is a ubiquitously expressed nuclear protein. It is found among several proteins that bind directly to retinoblastoma protein, which regulates cell proliferation. This protein complexes with transcriptional co-repressor CTBP. It is also associated with BRCA1 and is thought to modulate the functions of BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control. It is suggested that this gene may itself be a tumor suppressor acting in the same pathway as BRCA1. Three transcript variants encoding two different isoforms have been found for this gene. More transcript variants exist, but their full-length natures have not been determined. [provided by RefSeq, Jul 2008]

RBBP8 Gene-Disease associations (from GenCC):

Jawad syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
Seckel syndrome 2
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
Seckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RBBP8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068626404).

BP6

Variant 18-22993194-A-G is Benign according to our data. Variant chr18-22993194-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130103.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00176 (268/152356) while in subpopulation AMR AF = 0.00366 (56/15302). AF 95% confidence interval is 0.00289. There are 0 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBBP8	NM_002894.3 link	c.1367A>G	p.His456Arg	missense_variant	Exon 11 of 19	ENST00000327155.10	NP_002885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBBP8	ENST00000327155.10 link	c.1367A>G	p.His456Arg	missense_variant	Exon 11 of 19	1	NM_002894.3	ENSP00000323050.5

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00260

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00126

AC:

315

AN:

250606

AF XY:

0.00123

show subpopulations

Gnomad AFR exome

AF:

0.000315

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00219

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00198

AC:

2900

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

1403

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33464

American (AMR)

AF:

0.00150

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000497

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00237

AC:

2630

AN:

1111996

Other (OTH)

AF:

0.00260

AC:

157

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

195

390

585

780

975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.00176

AC:

268

AN:

152356

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

125

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41584

American (AMR)

AF:

0.00366

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00260

AC:

177

AN:

68042

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.00211

Hom.:

Bravo

AF:

0.00166

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00114

AC:

138

EpiCase

AF:

0.00262

EpiControl

AF:

0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

May 27, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 14, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RBBP8: BP4 -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RBBP8-related disorder

Benign:1

May 09, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.19

T;T;.;T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.60

.;T;T;T;T

M_CAP

Benign

0.0087

MetaRNN

Benign

0.0069

T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

1.2

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.6

N;N;N;N;N

REVEL

Benign

0.061

Sift

Benign

0.050

D;D;D;D;D

Sift4G

Benign

0.074

T;T;T;T;T

Polyphen

0.0

B;B;.;.;.

Vest4

0.16

MVP

0.26

MPC

0.051

ClinPred

0.019

GERP RS

3.6

PromoterAI

-0.0031

Neutral

(source)

Varity_R

0.053

gMVP

0.052

Mutation Taster

=83/17

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over