rs2075939

chr22-36875840-T-Achr22-36875840-T-Cchr22-36875840-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The ENST00000397147.7(NCF4):c.815T>A(p.Leu272Gln) 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. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L272P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NCF4 ENST00000397147.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.298

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08817622).
• BP6: Variant 22-36875840-T-A is Benign according to our data. Variant chr22-36875840-T-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.758+57T>A		intron_variant		ENST00000248899.11
NCF4	NM_013416.4	c.815T>A	p.Leu272Gln	missense_variant	8/9
NCF4	XM_047441384.1	c.932+57T>A		intron_variant
NCF4	XM_047441385.1	c.902+57T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.758+57T>A		intron_variant		1	NM_000631.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 85

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.036
Dann	Benign	0.95
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	0.56	N
REVEL	Benign	0.10
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Vest4		0.14
MutPred		0.24		Gain of disorder (P = 0.0412);
MVP		0.27
MPC		0.56
ClinPred		0.96	D
GERP RS		-0.74
gMVP		0.49

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: rs2075939; hg19: chr22-37271882;