chr22-36865055-C-T

Position:

• chr22-36865055-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000631.5(NCF4):​c.254C>T​(p.Thr85Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. T85N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NCF4 NM_000631.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0320

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056564897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.254C>T	p.Thr85Ile	missense_variant	3/10	ENST00000248899.11
NCF4-AS1	NR_147197.1	n.351+5038G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.254C>T	p.Thr85Ile	missense_variant	3/10	1	NM_000631.5	P1
NCF4-AS1	ENST00000619915.1	n.349+5038G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459798 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.26
DANN	Benign	0.69
DEOGEN2	Benign	0.079	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.26	N;N
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.54	N;N
REVEL	Benign	0.041
Sift	Benign	0.74	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0010	B;.
Vest4		0.069
MutPred		0.47		Gain of catalytic residue at P87 (P = 0.0541);Gain of catalytic residue at P87 (P = 0.0541);
MVP		0.28
MPC		0.19
ClinPred		0.025	T
GERP RS		-6.2
Varity_R		0.090
gMVP		0.19

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: rs112306225; hg19: chr22-37261097;