rs112306225

Positions:

• chr22-36865055-C-A
• chr22-36865055-C-T

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.254C>A​(p.Thr85Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,612,074 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (11 hom.)
• Consequence: NCF4 NM_000631.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00996235).
• BP6: Variant 22-36865055-C-A is Benign according to our data. Variant chr22-36865055-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 287656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36865055-C-A is described in Lovd as [Likely_benign]. Variant chr22-36865055-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00354 (539/152276) while in subpopulation AFR AF= 0.00864 (359/41548). AF 95% confidence interval is 0.0079. There are 1 homozygotes in gnomad4. There are 270 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.254C>A	p.Thr85Asn	missense_variant	3/10	ENST00000248899.11
NCF4-AS1	NR_147197.1	n.351+5038G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.254C>A	p.Thr85Asn	missense_variant	3/10	1	NM_000631.5	P1
NCF4-AS1	ENST00000619915.1	n.349+5038G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 535 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00857

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00231 AC: 575 AN: 248874 Hom.: 6 AF XY: 0.00200 AC XY: 269 AN XY: 134820

Gnomad AFR exome AF: 0.00875

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00320

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00198 AC: 2892 AN: 1459798 Hom.: 11 Cov.: 32 AF XY: 0.00184 AC XY: 1334 AN XY: 726318

Gnomad4 AFR exome AF: 0.00833

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00346

Gnomad4 NFE exome AF: 0.00198

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00354 AC: 539 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00363 AC XY: 270 AN XY: 74450

Gnomad4 AFR AF: 0.00864

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00166 Hom.: 1

Bravo AF: 0.00396

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00285 AC: 346

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2022	Variant summary: NCF4 c.254C>A (p.Thr85Asn) results in a non-conservative amino acid change located in the Phox homology domain (IPR001683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 248874 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 9.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in NCF4 causing Chronic Granulomatous Disease phenotype (0.00025), strongly suggesting that the variant is benign. Although reported among polymorphisms and not among hematologically important mutations in a recent mutational update (example, Roos_2021), to our knowledge, no occurrence of c.254C>A in individuals affected with Chronic Granulomatous Disease and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	NCF4: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2020	This variant is associated with the following publications: (PMID: 29454792) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.42
DANN	Benign	0.92
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.36	T;T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.87	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.78	N;N
REVEL	Benign	0.053
Sift	Benign	0.51	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.0	B;.
Vest4		0.097
MVP		0.40
MPC		0.20
ClinPred		0.00031	T
GERP RS		-6.2
Varity_R		0.17
gMVP		0.26

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;