1-183555720-C-A

Position:

• chr1-183555720-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000433.4(NCF2):​c.*398G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.9 in 206,112 control chromosomes in the GnomAD database, including 83,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (61969 hom., cov: 31)
  • Exomes 𝑓: 0.89 (21677 hom.)
• Consequence: NCF2 NM_000433.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.05

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-183555720-C-A is Benign according to our data. Variant chr1-183555720-C-A is described in ClinVar as [Benign]. Clinvar id is 294066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF2	NM_000433.4	c.*398G>T		3_prime_UTR_variant	15/15	ENST00000367535.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF2	ENST00000367535.8	c.*398G>T		3_prime_UTR_variant	15/15	1	NM_000433.4	P1

Frequencies

GnomAD3 genomes AF: 0.902 AC: 137087 AN: 152042 Hom.: 61925 Cov.: 31

Gnomad AFR AF: 0.938

Gnomad AMI AF: 0.908

Gnomad AMR AF: 0.895

Gnomad ASJ AF: 0.780

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.948

Gnomad FIN AF: 0.908

Gnomad MID AF: 0.798

Gnomad NFE AF: 0.877

Gnomad OTH AF: 0.870

GnomAD4 exome AF: 0.895 AC: 48265 AN: 53952 Hom.: 21677 Cov.: 0 AF XY: 0.897 AC XY: 25458 AN XY: 28366

Gnomad4 AFR exome AF: 0.948

Gnomad4 AMR exome AF: 0.916

Gnomad4 ASJ exome AF: 0.770

Gnomad4 EAS exome AF: 0.992

Gnomad4 SAS exome AF: 0.939

Gnomad4 FIN exome AF: 0.905

Gnomad4 NFE exome AF: 0.876

Gnomad4 OTH exome AF: 0.877

GnomAD4 genome AF: 0.902 AC: 137186 AN: 152160 Hom.: 61969 Cov.: 31 AF XY: 0.904 AC XY: 67221 AN XY: 74392

Gnomad4 AFR AF: 0.937

Gnomad4 AMR AF: 0.895

Gnomad4 ASJ AF: 0.780

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.947

Gnomad4 FIN AF: 0.908

Gnomad4 NFE AF: 0.877

Gnomad4 OTH AF: 0.866

Alfa AF: 0.874 Hom.: 69217

Bravo AF: 0.903

Asia WGS AF: 0.946 AC: 3290 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.32
DANN	Benign	0.42

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: rs796860; hg19: chr1-183524855;