rs4474794

Variant names:

• chr18-22987010-C-A
• rs4474794
• NM_002894.3:c.709+2020C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-22987010-C-A
• chr18-22987010-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002894.3(RBBP8):​c.709+2020C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 152,064 control chromosomes in the GnomAD database, including 21,359 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (21359 hom., cov: 32)
• Consequence: RBBP8 NM_002894.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0840
• Publications: 7 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

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.709+2020C>A		intron	N/A	NP_002885.1	Q99708-1
	RBBP8	NM_203291.2		c.709+2020C>A		intron	N/A	NP_976036.1	Q99708-1
	RBBP8	NM_203292.2		c.709+2020C>A		intron	N/A	NP_976037.1	Q99708-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP8	ENST00000327155.10	TSL:1 MANE Select	c.709+2020C>A		intron	N/A	ENSP00000323050.5	Q99708-1
	RBBP8	ENST00000360790.9	TSL:1	c.709+2020C>A		intron	N/A	ENSP00000354024.5	I6L8A6
	RBBP8	ENST00000399722.6	TSL:1	c.709+2020C>A		intron	N/A	ENSP00000382628.2	Q99708-1

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74135 AN: 151946 Hom.: 21361 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.557

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.487 AC: 74129 AN: 152064 Hom.: 21359 Cov.: 32 AF XY: 0.489 AC XY: 36327 AN XY: 74326

African (AFR) AF: 0.160 AC: 6656 AN: 41490

American (AMR) AF: 0.557 AC: 8517 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2346 AN: 3470

East Asian (EAS) AF: 0.474 AC: 2450 AN: 5170

South Asian (SAS) AF: 0.547 AC: 2632 AN: 4808

European-Finnish (FIN) AF: 0.598 AC: 6312 AN: 10564

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43372 AN: 67960

Other (OTH) AF: 0.554 AC: 1171 AN: 2114

Alfa AF: 0.578 Hom.: 13771

Bravo AF: 0.468

Asia WGS AF: 0.484 AC: 1683 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.38
PhyloP100		0.084
Mutation Taster		=100/0	polymorphism (auto)

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: rs4474794; hg19: chr18-20566973;