chr18-23022125-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_ModerateBS1_Supporting

The NM_002894.3(RBBP8):c.2455-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,590,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

RBBP8
NM_002894.3 splice_region, intron

Scores

Splicing: ADA: 0.9997

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.64

Publications

0 publications found

Variant links:

COSMIC-nc: COSV105890783

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 1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000115 (166/1438200) while in subpopulation MID AF = 0.000525 (3/5718). AF 95% confidence interval is 0.000142. There are 0 homozygotes in GnomAdExome4. There are 85 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBBP8	NM_002894.3 link	c.2455-4T>G		splice_region_variant, intron_variant	Intron 17 of 18	ENST00000327155.10	NP_002885.1	Q99708-1A0A024RC34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBBP8	ENST00000327155.10 link	c.2455-4T>G		splice_region_variant, intron_variant	Intron 17 of 18	1	NM_002894.3	ENSP00000323050.5		Q99708-1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000123

AC:

AN:

251200

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000115

AC:

166

AN:

1438200

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

717074

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32940

American (AMR)

AF:

0.00

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26008

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.000117

AC:

AN:

85656

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.000525

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000130

AC:

142

AN:

1090578

Other (OTH)

AF:

0.000151

AC:

AN:

59704

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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

AF:

0.0000855

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41408

American (AMR)

AF:

0.0000655

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

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:

0.000103

Hom.:

Bravo

AF:

0.000102

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jun 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 17 of the RBBP8 gene. It does not directly change the encoded amino acid sequence of the RBBP8 protein. This variant is present in population databases (rs374660795, gnomAD 0.02%). This variant has been observed in individual(s) with arthrogryposis multiplex congenita (PMID: 24319099). ClinVar contains an entry for this variant (Variation ID: 212021). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 20, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2455-4 T>G splice site variant in the RBBP8 gene has been reported previously as a homozygous variant in an individual with arthrogryposis multiplex, hypo/akinesia, pterygium, micrognathia, cleft palate, and hygroma (Laquerriere et al., 2014). The c.2455-4 T>G variant is observed in 26/111606 (0.2%) alleles from individuals of European background (Lek et al., 2016). This variant is predicted to reduce the quality of the splice acceptor site in intron 17. Functional studies demonstrate skipping of the adjacent exon 18, leading to a frameshift and stop codon (Laquerriere et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not specified

Uncertain:2

Apr 28, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.57

PhyloP100

1.6

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.46

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: 1

DS_AL_spliceai

0.46

Position offset: 4

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