NM_000433.4:c.1184G>A

Variant names:

• chr1-183563301-C-T
• rs145229115
• NM_000433.4:c.1184G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000433.4(NCF2):​c.1184G>A​(p.Arg395Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,050 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R395W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: NCF2 NM_000433.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 0.481
• Publications: 5 publications found

Genes affected

NCF2 (HGNC:7661): (neutrophil cytosolic factor 2) This gene encodes neutrophil cytosolic factor 2, the 67-kilodalton cytosolic subunit of the multi-protein NADPH oxidase complex found in neutrophils. This oxidase produces a burst of superoxide which is delivered to the lumen of the neutrophil phagosome. Mutations in this gene, as well as in other NADPH oxidase subunits, can result in chronic granulomatous disease, a disease that causes recurrent infections by catalase-positive organisms. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2010]

SMG7 (HGNC:16792): (SMG7 nonsense mediated mRNA decay factor) This gene encodes a protein that is essential for nonsense-mediated mRNA decay (NMD); a process whereby transcripts with premature termination codons are targeted for rapid degradation by a mRNA decay complex. The mRNA decay complex consists, in part, of this protein along with proteins SMG5 and UPF1. The N-terminal domain of this protein is thought to mediate its association with SMG5 or UPF1 while the C-terminal domain interacts with the mRNA decay complex. This protein may therefore couple changes in UPF1 phosphorylation state to the degradation of NMD-candidate transcripts. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2011]

SMG7 Gene-Disease associations (from GenCC):

• autoimmune disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013055384).
• BP6: Variant 1-183563301-C-T is Benign according to our data. Variant chr1-183563301-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 294080.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00123 (187/152242) while in subpopulation NFE AF = 0.00206 (140/68018). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000433.4. 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
	NCF2	NM_000433.4	MANE Select	c.1184G>A	p.Arg395Gln	missense	Exon 13 of 15	NP_000424.2
	NCF2	NM_001127651.3		c.1184G>A	p.Arg395Gln	missense	Exon 14 of 16	NP_001121123.1
	NCF2	NM_001410895.1		c.1076G>A	p.Arg359Gln	missense	Exon 13 of 15	NP_001397824.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF2	ENST00000367535.8	TSL:1 MANE Select	c.1184G>A	p.Arg395Gln	missense	Exon 13 of 15	ENSP00000356505.4
	NCF2	ENST00000367536.5	TSL:1	c.1184G>A	p.Arg395Gln	missense	Exon 14 of 16	ENSP00000356506.1
	NCF2	ENST00000697330.1		c.1184G>A	p.Arg395Gln	missense	Exon 14 of 16	ENSP00000513258.1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00114 AC: 286 AN: 251366 AF XY: 0.00113

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00181 AC: 2642 AN: 1461808 Hom.: 3 Cov.: 32 AF XY: 0.00178 AC XY: 1294 AN XY: 727206

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000850 AC: 38 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00226 AC: 2512 AN: 1111990

Other (OTH) AF: 0.00116 AC: 70 AN: 60390

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74440

African (AFR) AF: 0.000602 AC: 25 AN: 41550

American (AMR) AF: 0.00124 AC: 19 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00188 Hom.: 1

Bravo AF: 0.00125

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00106 AC: 129

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

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

May 01, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in individuals with inflammatory bowel disease in published literature (PMID: 29454792, 32463623); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24163247, 34547651, 29454792, 32463623)

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 Uncertain:1 Benign:2

Oct 13, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in association with Crohn's disease and inflammatory bowel disease (Denson 2018 PMID: 29454792; Ashton 2020 PMID: 32463623). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.2% [140/68026]; https://gnomad.broadinstitute.org/variant/1-183563301-C-T?dataset=gnomad_r3). It is also present in ClinVar, with several laboratories classifying it as benign or likely benign (Variation ID: 2248). Evolutionary conservation and computational predictive tools strongly suggest that this variant does not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NCF2-related disorder Uncertain:1

Sep 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NCF2 c.1184G>A variant is predicted to result in the amino acid substitution p.Arg395Gln. This variant has been reported in association with inflammatory bowel disease (Table 1, Denson et al. 2018. PubMed ID: 29454792; Table 2, Ashton et al. 2020. PubMed ID: 32463623). However, this variant is reported in 0.20% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-183532436-C-T), which may be too high to be causative. This variant also has conflicting interpretations regarding its pathogenic in ClinVar, ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/294080/). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.48
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.0090
Sift	Benign	0.19	T
Sift4G	Benign	0.21	T
Polyphen		0.034	B
Vest4		0.10
MVP		0.48
MPC		0.40
ClinPred		0.011	T
GERP RS		2.7
Varity_R		0.32
gMVP		0.39
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs145229115; hg19: chr1-183532436; COSMIC: COSV62314951;