18-22936854-G-A

Position:

• chr18-22936854-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_002894.3(RBBP8):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBBP8 NM_002894.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.80

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBBP8	NM_002894.3	c.3G>A	p.Met1?	start_lost	2/19	ENST00000327155.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBBP8	ENST00000327155.10	c.3G>A	p.Met1?	start_lost	2/19	1	NM_002894.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2021

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with RBBP8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the RBBP8 mRNA. The next in-frame methionine is located at codon 99. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Benign	0.73	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;D;.;.;.
Vest4		0.80, 0.82, 0.79
MutPred		0.51		Gain of catalytic residue at M1 (P = 0.1081);Gain of catalytic residue at M1 (P = 0.1081);Gain of catalytic residue at M1 (P = 0.1081);Gain of catalytic residue at M1 (P = 0.1081);Gain of catalytic residue at M1 (P = 0.1081);Gain of catalytic residue at M1 (P = 0.1081);Gain of catalytic residue at M1 (P = 0.1081);Gain of catalytic residue at M1 (P = 0.1081);Gain of catalytic residue at M1 (P = 0.1081);Gain of catalytic residue at M1 (P = 0.1081);
MVP		0.58
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.85
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-20516817;