1-183590217-C-T

Variant names:

• chr1-183590217-C-T
• rs147415774
• NM_000433.4:c.113G>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.113G>A​(p.Arg38Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0014 in 1,614,170 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts 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. R38W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (7 hom.)
• Consequence: NCF2 NM_000433.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 4.28
• Publications: 10 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=0.02710116).
• BP6: Variant 1-183590217-C-T is Benign according to our data. Variant chr1-183590217-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287151.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00145 (221/152278) while in subpopulation AMR AF = 0.00359 (55/15304). AF 95% confidence interval is 0.00284. 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 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF2	NM_000433.4	MANE Select	c.113G>A	p.Arg38Gln	missense	Exon 1 of 15	NP_000424.2	P19878-1
	NCF2	NM_001127651.3		c.113G>A	p.Arg38Gln	missense	Exon 2 of 16	NP_001121123.1	P19878-1
	NCF2	NM_001410895.1		c.113G>A	p.Arg38Gln	missense	Exon 2 of 15	NP_001397824.1	A0A8V8TMB9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF2	ENST00000367535.8	TSL:1 MANE Select	c.113G>A	p.Arg38Gln	missense	Exon 1 of 15	ENSP00000356505.4	P19878-1
	NCF2	ENST00000367536.5	TSL:1	c.113G>A	p.Arg38Gln	missense	Exon 2 of 16	ENSP00000356506.1	P19878-1
	NCF2	ENST00000946295.1		c.113G>A	p.Arg38Gln	missense	Exon 1 of 16	ENSP00000616354.1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00121 AC: 304 AN: 251480 AF XY: 0.00123

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00140 AC: 2044 AN: 1461892 Hom.: 7 Cov.: 31 AF XY: 0.00135 AC XY: 980 AN XY: 727246

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000984 AC: 44 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00163 AC: 1816 AN: 1112012

Other (OTH) AF: 0.00124 AC: 75 AN: 60396

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74448

African (AFR) AF: 0.000217 AC: 9 AN: 41548

American (AMR) AF: 0.00359 AC: 55 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00197 AC: 134 AN: 68020

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00143 Hom.: 1

Bravo AF: 0.00131

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00145 AC: 176

EpiCase AF: 0.000654

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	1	1	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (2)
-	-	1	NCF2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.027	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.3
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.59
Sift	Benign	0.033	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.35
MVP		0.85
MPC		1.1
ClinPred		0.18	T
GERP RS		5.0
PromoterAI		-0.027	Neutral
Varity_R		0.65
gMVP		0.38
Mutation Taster		=98/2	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: rs147415774; hg19: chr1-183559352;