chr22-36870535-C-T

Variant names:

• chr22-36870535-C-T
• rs758154907
• NM_000631.5:c.463C>T

Variant summary

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

The NM_000631.5(NCF4):​c.463C>T​(p.Arg155Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,459,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R155G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: NCF4 NM_000631.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.47

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-AS1 (HGNC:40393): (NCF4 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF4	NM_000631.5	c.463C>T	p.Arg155Trp	missense_variant	Exon 5 of 10	ENST00000248899.11	NP_000622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11	c.463C>T	p.Arg155Trp	missense_variant	Exon 5 of 10	1	NM_000631.5	ENSP00000248899.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459684 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726266

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33474

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86250

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51276

Gnomad4 NFE exome AF: 0.00000719 AC: 8 AN: 1111984

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.1	.;M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.74, 0.48
MutPred		0.44		.;Loss of disorder (P = 0.0015);Loss of disorder (P = 0.0015);
MVP		0.94
MPC		0.70
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.14
gMVP		0.70
Mutation Taster		=34/66	disease causing

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

Publications

LitVar

Other links and lift over

dbSNP: rs758154907; hg19: chr22-37266577;