18-22982330-A-G

Variant names:

• chr18-22982330-A-G
• rs748972422
• NM_002894.3:c.541A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002894.3(RBBP8):​c.541A>G​(p.Asn181Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. N181Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RBBP8 NM_002894.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.47
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2998017).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP8	NM_002894.3	MANE Select	c.541A>G	p.Asn181Asp	missense	Exon 7 of 19	NP_002885.1
	RBBP8	NM_203291.2		c.541A>G	p.Asn181Asp	missense	Exon 7 of 19	NP_976036.1
	RBBP8	NM_203292.2		c.541A>G	p.Asn181Asp	missense	Exon 7 of 18	NP_976037.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP8	ENST00000327155.10	TSL:1 MANE Select	c.541A>G	p.Asn181Asp	missense	Exon 7 of 19	ENSP00000323050.5
	RBBP8	ENST00000360790.9	TSL:1	c.541A>G	p.Asn181Asp	missense	Exon 7 of 19	ENSP00000354024.5
	RBBP8	ENST00000399722.6	TSL:1	c.541A>G	p.Asn181Asp	missense	Exon 7 of 19	ENSP00000382628.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.65	T
PhyloP100		5.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.50
MutPred		0.35		Gain of sheet (P = 4e-04)
MVP		0.44
MPC		0.070
ClinPred		0.88	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.14
Mutation Taster		=78/22	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: rs748972422; hg19: chr18-20562293;