rs201881905

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000631.5(NCF4):c.271+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,608,110 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 7 hom. )

Consequence

NCF4
NM_000631.5 splice_region, intron

Scores

Splicing: ADA: 0.000009096

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.51

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 22-36865079-G-A is Benign according to our data. Variant chr22-36865079-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 288902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36865079-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00124 (188/152140) while in subpopulation NFE AF= 0.00154 (105/67972). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF4	NM_000631.5 link	c.271+7G>A		splice_region_variant, intron_variant	Intron 3 of 9	ENST00000248899.11	NP_000622.2	Q15080-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF4	ENST00000248899.11 link	c.271+7G>A		splice_region_variant, intron_variant	Intron 3 of 9	1	NM_000631.5	ENSP00000248899.6		Q15080-1

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

188

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00154

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00187

AC:

459

AN:

244990

Hom.:

AF XY:

0.00178

AC XY:

237

AN XY:

133010

show subpopulations

Gnomad AFR exome

AF:

0.000310

Gnomad AMR exome

AF:

0.00206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00141

Gnomad FIN exome

AF:

0.00356

Gnomad NFE exome

AF:

0.00228

Gnomad OTH exome

AF:

0.00379

GnomAD4 exome

AF:

0.00183

AC:

2664

AN:

1455970

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

1255

AN XY:

724486

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00107

Gnomad4 FIN exome

AF:

0.00364

Gnomad4 NFE exome

AF:

0.00198

Gnomad4 OTH exome

AF:

0.00179

GnomAD4 genome

AF:

0.00124

AC:

188

AN:

152140

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000554

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00424

Gnomad4 NFE

AF:

0.00154

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.00102

Asia WGS

AF:

0.00231

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NCF4: BP4, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Jun 23, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.20

DANN

Benign

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000091

dbscSNV1_RF

Benign

0.0020

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

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