1-183555843-G-GGAA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000433.4(NCF2):c.*274_*275insTTC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 518,664 control chromosomes in the GnomAD database, including 79 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 31)
  • Exomes 𝑓: 0.016 (59 hom.)
• Consequence: NCF2 NM_000433.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0690

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 -10 ACMG points.

• BP6: Variant 1-183555843-G-GGAA is Benign according to our data. Variant chr1-183555843-G-GGAA is described in ClinVar as [Likely_benign]. Clinvar id is 1186252.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0126 (1923/152068) while in subpopulation NFE AF= 0.0205 (1396/67968). AF 95% confidence interval is 0.0196. There are 20 homozygotes in gnomad4. There are 874 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF2	NM_000433.4	c.*274_*275insTTC		3_prime_UTR_variant	15/15	ENST00000367535.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF2	ENST00000367535.8	c.*274_*275insTTC		3_prime_UTR_variant	15/15	1	NM_000433.4	P1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1927 AN: 151950 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.00891

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00813

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0106

GnomAD4 exome AF: 0.0159 AC: 5840 AN: 366596 Hom.: 59 Cov.: 0 AF XY: 0.0159 AC XY: 3079 AN XY: 194254

Gnomad4 AFR exome AF: 0.00373

Gnomad4 AMR exome AF: 0.00741

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.00803

Gnomad4 NFE exome AF: 0.0206

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0126 AC: 1923 AN: 152068 Hom.: 20 Cov.: 31 AF XY: 0.0118 AC XY: 874 AN XY: 74348

Gnomad4 AFR AF: 0.00381

Gnomad4 AMR AF: 0.00890

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.00813

Gnomad4 NFE AF: 0.0205

Gnomad4 OTH AF: 0.0105

Alfa AF: 0.0138 Hom.: 2

Bravo AF: 0.0120

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34035622; hg19: chr1-183524978;