1-183555724-G-GT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_000433.4(NCF2):c.*393_*394insA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 199,442 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (0 hom.)
• Consequence: NCF2 NM_000433.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.88

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00148 (208/140360) while in subpopulation AFR AF= 0.00358 (144/40232). AF 95% confidence interval is 0.0031. There are 0 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF2	NM_000433.4	c.*393_*394insA		3_prime_UTR_variant	15/15	ENST00000367535.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF2	ENST00000367535.8	c.*393_*394insA		3_prime_UTR_variant	15/15	1	NM_000433.4	P1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 203 AN: 140254 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00135

Gnomad ASJ AF: 0.00251

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.00120

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00347

Gnomad NFE AF: 0.000423

Gnomad OTH AF: 0.00213

GnomAD4 exome AF: 0.00479 AC: 283 AN: 59082 Hom.: 0 Cov.: 0 AF XY: 0.00500 AC XY: 155 AN XY: 31004

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.00773

Gnomad4 EAS exome AF: 0.00460

Gnomad4 SAS exome AF: 0.00502

Gnomad4 FIN exome AF: 0.00389

Gnomad4 NFE exome AF: 0.00443

Gnomad4 OTH exome AF: 0.00542

GnomAD4 genome AF: 0.00148 AC: 208 AN: 140360 Hom.: 0 Cov.: 31 AF XY: 0.00133 AC XY: 91 AN XY: 68308

Gnomad4 AFR AF: 0.00358

Gnomad4 AMR AF: 0.00134

Gnomad4 ASJ AF: 0.00251

Gnomad4 EAS AF: 0.000202

Gnomad4 SAS AF: 0.000962

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000423

Gnomad4 OTH AF: 0.00263

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Chronic granulomatous disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs771465757; hg19: chr1-183524859;