NM_002894.3:c.109+6A>G

Variant names:

• chr18-22936966-A-G
• rs149189755
• NM_002894.3:c.109+6A>G

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.109+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,832 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (18 hom.)
• Consequence: RBBP8 NM_002894.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001176
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.250
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 18-22936966-A-G is Benign according to our data. Variant chr18-22936966-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00121 (184/152328) while in subpopulation SAS AF = 0.0116 (56/4830). AF 95% confidence interval is 0.00917. There are 0 homozygotes in GnomAd4. There are 96 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP8	NM_002894.3	MANE Select	c.109+6A>G		splice_region intron	N/A	NP_002885.1	Q99708-1
	RBBP8	NM_203291.2		c.109+6A>G		splice_region intron	N/A	NP_976036.1	Q99708-1
	RBBP8	NM_203292.2		c.109+6A>G		splice_region 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.109+6A>G		splice_region intron	N/A	ENSP00000323050.5	Q99708-1
	RBBP8	ENST00000360790.9	TSL:1	c.109+6A>G		splice_region intron	N/A	ENSP00000354024.5	I6L8A6
	RBBP8	ENST00000399722.6	TSL:1	c.109+6A>G		splice_region intron	N/A	ENSP00000382628.2	Q99708-1

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00292 AC: 733 AN: 250946 AF XY: 0.00354

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00161 AC: 2358 AN: 1461504 Hom.: 18 Cov.: 30 AF XY: 0.00207 AC XY: 1507 AN XY: 727050

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.00119 AC: 53 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 337 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.0135 AC: 1164 AN: 86252

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53186

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.000550 AC: 612 AN: 1111916

Other (OTH) AF: 0.00234 AC: 141 AN: 60384

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74488

African (AFR) AF: 0.0000962 AC: 4 AN: 41564

American (AMR) AF: 0.00176 AC: 27 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000661 AC: 45 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00128 Hom.: 1

Bravo AF: 0.00113

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	RBBP8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.3
DANN	Benign	0.73
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs149189755; hg19: chr18-20516929;