chr22-36870411-A-G

Variant names:

• chr22-36870411-A-G
• rs79312013
• NM_000631.5:c.343-4A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000631.5(NCF4):​c.343-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,613,768 control chromosomes in the GnomAD database, including 20 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 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (16 hom.)
• Consequence: NCF4 NM_000631.5 splice_region, intron
• Scores: Splicing: ADA: 0.0005640
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.50
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-36870411-A-G is Benign according to our data. Variant chr22-36870411-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 471812.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 = 0.00329 (501/152204) while in subpopulation NFE AF = 0.0036 (245/68000). AF 95% confidence interval is 0.00323. There are 4 homozygotes in GnomAd4. There are 300 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000631.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	NM_000631.5	MANE Select	c.343-4A>G		splice_region intron	N/A	NP_000622.2
	NCF4	NM_013416.4		c.343-4A>G		splice_region intron	N/A	NP_038202.2	Q15080-3
	NCF4-AS1	NR_147197.1		n.33T>C		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	ENST00000248899.11	TSL:1 MANE Select	c.343-4A>G		splice_region intron	N/A	ENSP00000248899.6	Q15080-1
	NCF4	ENST00000397147.7	TSL:1	c.343-4A>G		splice_region intron	N/A	ENSP00000380334.4	Q15080-3
	NCF4	ENST00000650698.1		c.34-4A>G		splice_region intron	N/A	ENSP00000498381.1	A0A494BZS1

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 501 AN: 152086 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00308 AC: 774 AN: 251056 AF XY: 0.00309

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00305 AC: 4464 AN: 1461564 Hom.: 16 Cov.: 32 AF XY: 0.00303 AC XY: 2203 AN XY: 727088

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.00119 AC: 53 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00731 AC: 191 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86258

European-Finnish (FIN) AF: 0.0155 AC: 823 AN: 53108

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00287 AC: 3193 AN: 1112000

Other (OTH) AF: 0.00245 AC: 148 AN: 60392

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152204 Hom.: 4 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74420

African (AFR) AF: 0.000409 AC: 17 AN: 41534

American (AMR) AF: 0.00131 AC: 20 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.0189 AC: 200 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00360 AC: 245 AN: 68000

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00287 Hom.: 3

Bravo AF: 0.00190

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (1)
-	-	1	NCF4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.055
DANN	Benign	0.59
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.10
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

Other links and lift over

dbSNP: rs79312013; hg19: chr22-37266453;