22-36861077-C-A

Variant names:

• chr22-36861077-C-A
• rs148141762
• NM_000631.5:c.-95C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000631.5(NCF4):​c.-95C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,347,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: NCF4 NM_000631.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69
• 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-AS1 (HGNC:40393): (NCF4 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF4	NM_000631.5	c.-95C>A		5_prime_UTR_variant	Exon 1 of 10	ENST00000248899.11	NP_000622.2
NCF4	NM_013416.4	c.-95C>A		5_prime_UTR_variant	Exon 1 of 9		NP_038202.2
NCF4-AS1	NR_147197.1	n.351+9016G>T		intron_variant	Intron 1 of 1
NCF4	XM_047441385.1	c.-642C>A		upstream_gene_variant			XP_047297341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11	c.-95C>A		5_prime_UTR_variant	Exon 1 of 10	1	NM_000631.5	ENSP00000248899.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1347312 Hom.: 0 Cov.: 26 AF XY: 0.00000150 AC XY: 1 AN XY: 667270

African (AFR) AF: 0.00 AC: 0 AN: 30590

American (AMR) AF: 0.0000281 AC: 1 AN: 35632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24900

East Asian (EAS) AF: 0.00 AC: 0 AN: 35486

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4788

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1032394

Other (OTH) AF: 0.00 AC: 0 AN: 56222

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.096
DANN	Benign	0.69
PhyloP100		-2.7
PromoterAI		-0.0069	Neutral

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: rs148141762; hg19: chr22-37257119;