rs139743319

Positions:

• chr18-22993194-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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. 14/20 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.18

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]

ACMG classification

Verdict is Benign. Variant got -9 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 id is 130103.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr18-22993194-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBBP8	NM_002894.3	c.1367A>G	p.His456Arg	missense_variant	11/19	ENST00000327155.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBBP8	ENST00000327155.10	c.1367A>G	p.His456Arg	missense_variant	11/19	1	NM_002894.3	P1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152238 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.00126 AC: 315 AN: 250606 Hom.: 0 AF XY: 0.00123 AC XY: 167 AN XY: 135748

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 SAS exome AF: 0.0000980

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.: 5 Cov.: 32 AF XY: 0.00193 AC XY: 1403 AN XY: 727232

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00237

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.00168 AC XY: 125 AN XY: 74504

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00260

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00219 Hom.: 1

Bravo AF: 0.00166

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00114 AC: 138

EpiCase AF: 0.00262

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 14, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

RBBP8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2022

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	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
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	D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.0069	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.72	N;N;N;N
PrimateAI	Benign	0.38	T
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	T
GERP RS		3.6
Varity_R		0.053
gMVP		0.052

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

LitVar

Other links and lift over

dbSNP: rs139743319; hg19: chr18-20573157; COSMIC: COSV105231597; COSMIC: COSV105231597;