X-16852858-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002893.4(RBBP7):​c.776A>C​(p.Asn259Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 111,763 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. N259S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: RBBP7 NM_002893.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20060816).

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>C	p.Asn259Thr	missense	Exon 7 of 12	NP_002884.1	Q6FHQ0
	RBBP7	NM_001198719.2		c.908A>C	p.Asn303Thr	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>C	p.Asn259Thr	missense	Exon 7 of 12	ENSP00000369427.3	Q16576-1
	RBBP7	ENST00000486166.1	TSL:1	n.1229A>C		non_coding_transcript_exon	Exon 3 of 3
	RBBP7	ENST00000380084.8	TSL:2	c.908A>C	p.Asn303Thr	missense	Exon 7 of 12	ENSP00000369424.4	Q16576-2

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111709 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183192 AF XY: 0.00

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111763 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33957

African (AFR) AF: 0.0000326 AC: 1 AN: 30719

American (AMR) AF: 0.00 AC: 0 AN: 10523

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2693

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6063

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53130

Other (OTH) AF: 0.00 AC: 0 AN: 1518

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.7	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.45	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.64
MVP		0.86
MPC		2.3
ClinPred		0.40	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.68
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs190827851; hg19: chrX-16870981;