dbSNP rs373804633: RBBP8:p.Arg100Gly (chr18-22968855-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_002894.3(RBBP8):c.298C>G(p.Arg100Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,192 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R100W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RBBP8
NM_002894.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.04

Publications

12 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-22968855-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127245.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBBP8	NM_002894.3 link	c.298C>G	p.Arg100Gly	missense_variant	Exon 5 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.298C>G	p.Arg100Gly	missense_variant	Exon 5 of 19	1	NM_002894.3	ENSP00000323050.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251218

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461192

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726910

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39576

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111596

Other (OTH)

AF:

0.00

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000149

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;D;D;.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;.;D;D;D;D

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.57

D;D;D;D;D;D

MetaSVM

Benign

-0.78

PhyloP100

2.0

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.1

.;D;D;D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

.;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D

Polyphen

0.96

.;D;D;.;.;.

Vest4

0.72, 0.61, 0.73

MutPred

0.62

Loss of MoRF binding (P = 0.0434);Loss of MoRF binding (P = 0.0434);Loss of MoRF binding (P = 0.0434);Loss of MoRF binding (P = 0.0434);Loss of MoRF binding (P = 0.0434);Loss of MoRF binding (P = 0.0434);

MVP

0.51

MPC

0.31

ClinPred

0.97

GERP RS

3.5

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.67

gMVP

0.096

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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