rs150103256

chr22-36871659-G-Achr22-36871659-G-C

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.478G>A(p.Val160Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,570,010 control chromosomes in the GnomAD database, including 11 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 0.0012 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: NCF4 NM_000631.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0690

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 (MetaRNN=0.003737539).
• BP6: Variant 22-36871659-G-A is Benign according to our data. Variant chr22-36871659-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 341554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36871659-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00123 (187/152366) while in subpopulation SAS AF= 0.0101 (49/4834). AF 95% confidence interval is 0.00788. There are 3 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5	c.478G>A	p.Val160Met	missense_variant	6/10	ENST00000248899.11
NCF4	NM_013416.4	c.478G>A	p.Val160Met	missense_variant	6/9
NCF4	XM_047441384.1	c.652G>A	p.Val218Met	missense_variant	7/11
NCF4	XM_047441385.1	c.622G>A	p.Val208Met	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11	c.478G>A	p.Val160Met	missense_variant	6/10	1	NM_000631.5	P1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152248 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00176 AC: 324 AN: 184276 Hom.: 3 AF XY: 0.00194 AC XY: 190 AN XY: 98110

Gnomad AFR exome AF: 0.000632

Gnomad AMR exome AF: 0.000362

Gnomad ASJ exome AF: 0.00282

Gnomad EAS exome AF: 0.00212

Gnomad SAS exome AF: 0.00766

Gnomad FIN exome AF: 0.0000599

Gnomad NFE exome AF: 0.000705

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00112 AC: 1587 AN: 1417644 Hom.: 8 Cov.: 31 AF XY: 0.00129 AC XY: 907 AN XY: 700982

Gnomad4 AFR exome AF: 0.000246

Gnomad4 AMR exome AF: 0.000366

Gnomad4 ASJ exome AF: 0.00335

Gnomad4 EAS exome AF: 0.00324

Gnomad4 SAS exome AF: 0.00682

Gnomad4 FIN exome AF: 0.0000796

Gnomad4 NFE exome AF: 0.000593

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152366 Hom.: 3 Cov.: 33 AF XY: 0.00136 AC XY: 101 AN XY: 74522

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.0101

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.000948

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.000584 AC: 5

ExAC AF: 0.00141 AC: 168

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2021

- -

NCF4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	9.2
Dann	Benign	0.84
DEOGEN2	Benign	0.024	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.48	T;T;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.50	N;N;N
REVEL	Benign	0.017
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.12	.;B;.
Vest4		0.12, 0.10
MVP		0.53
MPC		0.18
ClinPred		0.0011	T
GERP RS		-1.7
Varity_R		0.016
gMVP		0.28

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: rs150103256; hg19: chr22-37267701;