rs34373276

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000631.5(NCF4):c.63C>T(p.Ala21=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,614,132 control chromosomes in the GnomAD database, including 340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 190 hom., cov: 30)

Exomes 𝑓: 0.0027 ( 150 hom. )

Consequence

NCF4
NM_000631.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.242

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 22-36864075-C-T is Benign according to our data. Variant chr22-36864075-C-T is described in ClinVar as [Benign]. Clinvar id is 341548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36864075-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.242 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF4	NM_000631.5 linkuse as main transcript	c.63C>T	p.Ala21=	synonymous_variant	2/10	ENST00000248899.11
NCF4-AS1	NR_147197.1 linkuse as main transcript	n.351+6018G>A		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.63C>T	p.Ala21=	synonymous_variant	2/10	1	NM_000631.5	P1	Q15080-1
NCF4-AS1	ENST00000619915.1 linkuse as main transcript	n.349+6018G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3983

AN:

152146

Hom.:

189

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0911

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00955

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.0186

GnomAD3 exomes

AF:

0.00669

AC:

1683

AN:

251496

Hom.:

AF XY:

0.00488

AC XY:

663

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0915

Gnomad AMR exome

AF:

0.00416

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.00267

AC:

3902

AN:

1461868

Hom.:

150

Cov.:

AF XY:

0.00234

AC XY:

1703

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0941

Gnomad4 AMR exome

AF:

0.00472

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000145

Gnomad4 OTH exome

AF:

0.00586

GnomAD4 genome

AF:

0.0262

AC:

3987

AN:

152264

Hom.:

190

Cov.:

AF XY:

0.0257

AC XY:

1916

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0909

Gnomad4 AMR

AF:

0.00954

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.0184

Alfa

AF:

0.0174

Hom.:

Bravo

AF:

0.0305

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

Cadd

Benign

7.3

Dann

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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