rs112306225

Variant names:

• chr22-36865055-C-A
• rs112306225
• NM_000631.5:c.254C>A

Your query was ambiguous. Multiple possible variants found:

• chr22-36865055-C-A
• chr22-36865055-C-T

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.254C>A​(p.Thr85Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,612,074 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (11 hom.)
• Consequence: NCF4 NM_000631.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0320
• Publications: 8 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 (MetaRNN=0.00996235).
• BP6: Variant 22-36865055-C-A is Benign according to our data. Variant chr22-36865055-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 287656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00354 (539/152276) while in subpopulation AFR AF = 0.00864 (359/41548). AF 95% confidence interval is 0.0079. There are 1 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	NM_000631.5	MANE Select	c.254C>A	p.Thr85Asn	missense	Exon 3 of 10	NP_000622.2
	NCF4	NM_013416.4		c.254C>A	p.Thr85Asn	missense	Exon 3 of 9	NP_038202.2
	NCF4-AS1	NR_147197.1		n.351+5038G>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF4	ENST00000248899.11	TSL:1 MANE Select	c.254C>A	p.Thr85Asn	missense	Exon 3 of 10	ENSP00000248899.6
	NCF4	ENST00000397147.7	TSL:1	c.254C>A	p.Thr85Asn	missense	Exon 3 of 9	ENSP00000380334.4
	NCF4	ENST00000651053.1		n.559C>A		non_coding_transcript_exon	Exon 4 of 11

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 535 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00857

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00231 AC: 575 AN: 248874 AF XY: 0.00200

Gnomad AFR exome AF: 0.00875

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00320

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00198 AC: 2892 AN: 1459798 Hom.: 11 Cov.: 32 AF XY: 0.00184 AC XY: 1334 AN XY: 726318

African (AFR) AF: 0.00833 AC: 279 AN: 33476

American (AMR) AF: 0.00199 AC: 89 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00346 AC: 178 AN: 51458

Middle Eastern (MID) AF: 0.000702 AC: 4 AN: 5698

European-Non Finnish (NFE) AF: 0.00198 AC: 2202 AN: 1111984

Other (OTH) AF: 0.00222 AC: 134 AN: 60370

GnomAD4 genome AF: 0.00354 AC: 539 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00363 AC XY: 270 AN XY: 74450

African (AFR) AF: 0.00864 AC: 359 AN: 41548

American (AMR) AF: 0.00157 AC: 24 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00219 Hom.: 2

Bravo AF: 0.00396

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00285 AC: 346

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00166

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.42
DANN	Benign	0.92
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.87	L
PhyloP100		0.032
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.053
Sift	Benign	0.51	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.097
MVP		0.40
MPC		0.20
ClinPred		0.00031	T
GERP RS		-6.2
Varity_R		0.17
gMVP		0.26
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs112306225; hg19: chr22-37261097;