rs56071149

Positions:

• chr22-36875639-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000631.5(NCF4):​c.628-14C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,609,904 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (13 hom., cov: 32)
  • Exomes 𝑓: 0.018 (291 hom.)
• Consequence: NCF4 NM_000631.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.657

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-36875639-C-A is Benign according to our data. Variant chr22-36875639-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 260305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.012 (1829/152256) while in subpopulation SAS AF= 0.0278 (134/4812). AF 95% confidence interval is 0.024. There are 13 homozygotes in gnomad4. There are 862 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.628-14C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000248899.11
NCF4	NM_013416.4	c.628-14C>A		splice_polypyrimidine_tract_variant, intron_variant
NCF4	XM_047441384.1	c.802-14C>A		splice_polypyrimidine_tract_variant, intron_variant
NCF4	XM_047441385.1	c.772-14C>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.628-14C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000631.5	P1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1832 AN: 152138 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0152 AC: 3762 AN: 247390 Hom.: 39 AF XY: 0.0164 AC XY: 2202 AN XY: 134140

Gnomad AFR exome AF: 0.00231

Gnomad AMR exome AF: 0.00654

Gnomad ASJ exome AF: 0.0411

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0257

Gnomad FIN exome AF: 0.00478

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0178 AC: 26013 AN: 1457648 Hom.: 291 Cov.: 31 AF XY: 0.0184 AC XY: 13313 AN XY: 725292

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.00740

Gnomad4 ASJ exome AF: 0.0399

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0288

Gnomad4 FIN exome AF: 0.00563

Gnomad4 NFE exome AF: 0.0183

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome AF: 0.0120 AC: 1829 AN: 152256 Hom.: 13 Cov.: 32 AF XY: 0.0116 AC XY: 862 AN XY: 74458

Gnomad4 AFR AF: 0.00282

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0278

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.0187 Hom.: 8

Bravo AF: 0.0114

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.7
DANN	Benign	0.71

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: rs56071149; hg19: chr22-37271681;