1-183555724-GT-G

Variant summary

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

The NM_000433.4(NCF2):c.*393del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 199,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (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 sas. gnomad4_exome allele frequency = 0.000386 (23/59576) while in subpopulation SAS AF= 0.000524 (4/7636). AF 95% confidence interval is 0.00026. There are 0 homozygotes in gnomad4_exome. There are 19 alleles in male gnomad4_exome subpopulation. Median coverage is 0. 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.*393del		3_prime_UTR_variant	15/15	ENST00000367535.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000200 AC: 28 AN: 140252 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00125

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000239

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000276

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000386 AC: 23 AN: 59576 Hom.: 0 Cov.: 0 AF XY: 0.000608 AC XY: 19 AN XY: 31252

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000274

Gnomad4 ASJ exome AF: 0.00128

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000524

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000422

Gnomad4 OTH exome AF: 0.000317

GnomAD4 genome AF: 0.000200 AC: 28 AN: 140252 Hom.: 0 Cov.: 31 AF XY: 0.000191 AC XY: 13 AN XY: 68188

Gnomad4 AFR AF: 0.000150

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00125

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000239

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000276

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000178

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

- -

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;