chr22-36865079-G-A

Variant summary

Our verdict is Benign. The variant received -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

2
Splicing: ADA: 0.000009096
2

Clinical Significance

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

Conservation

PhyloP100: -3.51

Publications

0 publications found
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-AS1 (HGNC:40393): (NCF4 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.
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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NCF4NM_000631.5 linkc.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
NCF4ENST00000248899.11 linkc.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.:
0
Cov.:
31
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
GnomAD2 exomes
AF:
0.00187
AC:
459
AN:
244990
AF XY:
0.00178
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 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.:
7
Cov.:
32
AF XY:
0.00173
AC XY:
1255
AN XY:
724486
show subpopulations
African (AFR)
AF:
0.000269
AC:
9
AN:
33458
American (AMR)
AF:
0.00165
AC:
74
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.000115
AC:
3
AN:
26136
East Asian (EAS)
AF:
0.0000756
AC:
3
AN:
39696
South Asian (SAS)
AF:
0.00107
AC:
92
AN:
86236
European-Finnish (FIN)
AF:
0.00364
AC:
175
AN:
48066
Middle Eastern (MID)
AF:
0.000184
AC:
1
AN:
5428
European-Non Finnish (NFE)
AF:
0.00198
AC:
2199
AN:
1111934
Other (OTH)
AF:
0.00179
AC:
108
AN:
60300
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.447
Heterozygous variant carriers
0
153
307
460
614
767
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
84
168
252
336
420
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00124
AC:
188
AN:
152140
Hom.:
0
Cov.:
31
AF XY:
0.00138
AC XY:
103
AN XY:
74382
show subpopulations
African (AFR)
AF:
0.000554
AC:
23
AN:
41496
American (AMR)
AF:
0.000589
AC:
9
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.000580
AC:
3
AN:
5170
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4826
European-Finnish (FIN)
AF:
0.00424
AC:
45
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.00154
AC:
105
AN:
67972
Other (OTH)
AF:
0.000474
AC:
1
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
10
20
31
41
51
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00114
Hom.:
0
Bravo
AF:
0.00102
Asia WGS
AF:
0.00231
AC:
8
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
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

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
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
PhyloP100
-3.5
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs201881905; hg19: chr22-37261121; API