chrX-16852858-T-C

Variant names:

• chrX-16852858-T-C
• rs190827851
• NM_002893.4:c.776A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002893.4(RBBP7):​c.776A>G​(p.Asn259Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,098,114 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000037 (0 hom. 11 hem.)
• Consequence: RBBP7 NM_002893.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01
• Publications: 2 publications found

Genes affected

RBBP7 (HGNC:9890): (RB binding protein 7, chromatin remodeling factor) This protein is a ubiquitously expressed nuclear protein and belongs to a highly conserved subfamily of WD-repeat proteins. It is found among several proteins that binds directly to retinoblastoma protein, which regulates cell proliferation. The encoded protein is found in many histone deacetylase complexes, including mSin3 co-repressor complex. It is also present in protein complexes involved in chromatin assembly. This protein can interact with BRCA1 tumor-suppressor gene and may have a role in the regulation of cell proliferation and differentiation. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

RBBP7 Gene-Disease associations (from GenCC):

• spermatogenic failure, X-linked, 9

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19357511).
• BS2: High Hemizygotes in GnomAdExome4 at 11 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002893.4. 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
	RBBP7	NM_002893.4	MANE Select	c.776A>G	p.Asn259Ser	missense	Exon 7 of 12	NP_002884.1	Q6FHQ0
	RBBP7	NM_001198719.2		c.908A>G	p.Asn303Ser	missense	Exon 7 of 12	NP_001185648.1	Q16576-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP7	ENST00000380087.7	TSL:1 MANE Select	c.776A>G	p.Asn259Ser	missense	Exon 7 of 12	ENSP00000369427.3	Q16576-1
	RBBP7	ENST00000486166.1	TSL:1	n.1229A>G		non_coding_transcript_exon	Exon 3 of 3
	RBBP7	ENST00000380084.8	TSL:2	c.908A>G	p.Asn303Ser	missense	Exon 7 of 12	ENSP00000369424.4	Q16576-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000491 AC: 9 AN: 183192 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000612

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000373 AC: 41 AN: 1098114 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 11 AN XY: 363502

African (AFR) AF: 0.0000379 AC: 1 AN: 26398

American (AMR) AF: 0.0000852 AC: 3 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4067

European-Non Finnish (NFE) AF: 0.0000416 AC: 35 AN: 842108

Other (OTH) AF: 0.00 AC: 0 AN: 46079

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.73	N
PhyloP100		8.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.12
Sift	Benign	0.75	T
Sift4G	Benign	0.87	T
Polyphen		0.0	B
Vest4		0.60
MutPred		0.24		Gain of disorder (P = 0.0478)
MVP		0.80
MPC		1.7
ClinPred		0.12	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.44
Mutation Taster		=84/16	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: rs190827851; hg19: chrX-16870981;