rs111445733

Variant names:

• chr18-22993593-G-A
• rs111445733
• NM_002894.3:c.1766G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002894.3(RBBP8):​c.1766G>A​(p.Arg589His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,614,148 control chromosomes in the GnomAD database, including 150 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R589R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0080 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (143 hom.)
• Consequence: RBBP8 NM_002894.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.137
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030443072).
• BP6: Variant 18-22993593-G-A is Benign according to our data. Variant chr18-22993593-G-A is described in ClinVar as Benign. ClinVar VariationId is 130105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00802 (1222/152306) while in subpopulation NFE AF = 0.0144 (977/68024). AF 95% confidence interval is 0.0136. There are 7 homozygotes in GnomAd4. There are 541 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002894.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP8	NM_002894.3	MANE Select	c.1766G>A	p.Arg589His	missense	Exon 11 of 19	NP_002885.1
	RBBP8	NM_203291.2		c.1766G>A	p.Arg589His	missense	Exon 11 of 19	NP_976036.1
	RBBP8	NM_203292.2		c.1766G>A	p.Arg589His	missense	Exon 11 of 18	NP_976037.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP8	ENST00000327155.10	TSL:1 MANE Select	c.1766G>A	p.Arg589His	missense	Exon 11 of 19	ENSP00000323050.5
	RBBP8	ENST00000360790.9	TSL:1	c.1766G>A	p.Arg589His	missense	Exon 11 of 19	ENSP00000354024.5
	RBBP8	ENST00000399722.6	TSL:1	c.1766G>A	p.Arg589His	missense	Exon 11 of 19	ENSP00000382628.2

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 1222 AN: 152186 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00714 AC: 1792 AN: 250904 AF XY: 0.00678

Gnomad AFR exome AF: 0.00218

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00508

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00704

GnomAD4 exome AF: 0.0118 AC: 17237 AN: 1461842 Hom.: 143 Cov.: 32 AF XY: 0.0114 AC XY: 8292 AN XY: 727226

African (AFR) AF: 0.00221 AC: 74 AN: 33468

American (AMR) AF: 0.00210 AC: 94 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00486 AC: 127 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86246

European-Finnish (FIN) AF: 0.00459 AC: 245 AN: 53412

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0144 AC: 16027 AN: 1112002

Other (OTH) AF: 0.00975 AC: 589 AN: 60394

GnomAD4 genome AF: 0.00802 AC: 1222 AN: 152306 Hom.: 7 Cov.: 32 AF XY: 0.00726 AC XY: 541 AN XY: 74474

African (AFR) AF: 0.00269 AC: 112 AN: 41572

American (AMR) AF: 0.00340 AC: 52 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00462 AC: 49 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0144 AC: 977 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.0107 Hom.: 21

Bravo AF: 0.00732

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.00707 AC: 858

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0125

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	RBBP8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.3
DANN	Benign	0.90
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.14
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.016
Sift	Benign	0.15	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.040
MPC		0.052
ClinPred		0.000030	T
GERP RS		-4.0
PromoterAI		0.0073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.043
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs111445733; hg19: chr18-20573556; COSMIC: COSV99045592; COSMIC: COSV99045592;