rs369847561

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000631.5(NCF4):c.179G>A(p.Arg60His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,614,012 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R60C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000069 ( 1 hom. )

Consequence

NCF4
NM_000631.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.49

Variant links:

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 links:

NCF4-AS1 (HGNC:40393): (NCF4 antisense RNA 1)

NCF4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5 linkuse as main transcript	c.179G>A	p.Arg60His	missense_variant	3/10	ENST00000248899.11
NCF4-AS1	NR_147197.1 linkuse as main transcript	n.351+5113C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF4	ENST00000248899.11 linkuse as main transcript	c.179G>A	p.Arg60His	missense_variant	3/10	1	NM_000631.5	P1	Q15080-1
NCF4-AS1	ENST00000619915.1 linkuse as main transcript	n.349+5113C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251336

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1461828

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000612

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000824

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 12, 2024

Variant summary: NCF4 c.179G>A (p.Arg60His) results in a non-conservative amino acid change located in the Phox homology domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251336 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NCF4 causing Chronic Granulomatous Disease (5.6e-05 vs 0.00025), allowing no conclusion about variant significance. c.179G>A has been reported in the literature in an individual affected with Crohn's disease in the heterozygous state (Wright_2019). This report does not provide unequivocal conclusions about association of the variant with Chronic Granulomatous Disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. ClinVar contains an entry for this variant (Variation ID: 539179). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 60 of the NCF4 protein (p.Arg60His). This variant is present in population databases (rs369847561, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of NCF4-related condition (PMID: 31027832). ClinVar contains an entry for this variant (Variation ID: 539179). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.27

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.64

D;D

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.25

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;.

Vest4

0.68

MVP

0.94

MPC

0.78

ClinPred

0.24

GERP RS

5.7

Varity_R

0.68

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over