chr22-36875730-C-A

Variant names:

• chr22-36875730-C-A
• rs150656826
• NM_000631.5:c.705C>A

Variant summary

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

The NM_000631.5(NCF4):​c.705C>A​(p.Asp235Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D235N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCF4 NM_000631.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.680
• Publications: 0 publications found

Genes affected

NCF4 (HGNC:7662): (neutrophil cytosolic factor 4) The protein encoded by this gene is a cytosolic regulatory component of the superoxide-producing phagocyte NADPH-oxidase, a multicomponent enzyme system important for host defense. This protein is preferentially expressed in cells of myeloid lineage. It interacts primarily with neutrophil cytosolic factor 2 (NCF2/p67-phox) to form a complex with neutrophil cytosolic factor 1 (NCF1/p47-phox), which further interacts with the small G protein RAC1 and translocates to the membrane upon cell stimulation. This complex then activates flavocytochrome b, the membrane-integrated catalytic core of the enzyme system. The PX domain of this protein can bind phospholipid products of the PI(3) kinase, which suggests its role in PI(3) kinase-mediated signaling events. The phosphorylation of this protein was found to negatively regulate the enzyme activity. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

NCF4 Gene-Disease associations (from GenCC):

• granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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=0.1647591).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000631.5. 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
	NCF4	NM_000631.5	MANE Select	c.705C>A	p.Asp235Glu	missense	Exon 8 of 10	NP_000622.2
	NCF4	NM_013416.4		c.705C>A	p.Asp235Glu	missense	Exon 8 of 9	NP_038202.2	Q15080-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	ENST00000248899.11	TSL:1 MANE Select	c.705C>A	p.Asp235Glu	missense	Exon 8 of 10	ENSP00000248899.6	Q15080-1
	NCF4	ENST00000397147.7	TSL:1	c.705C>A	p.Asp235Glu	missense	Exon 8 of 9	ENSP00000380334.4	Q15080-3
	NCF4	ENST00000650698.1		c.396C>A	p.Asp132Glu	missense	Exon 8 of 10	ENSP00000498381.1	A0A494BZS1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.68
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.099
Sift	Benign	0.19	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.30		Gain of catalytic residue at D235 (P = 0.0885)
MVP		0.86
MPC		0.67
ClinPred		0.72	D
GERP RS		3.3
Varity_R		0.091
gMVP		0.31
Mutation Taster		=93/7	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: rs150656826; hg19: chr22-37271772;