rs147744729

chr1-183563531-T-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000433.4(NCF2):c.1081A>T(p.Thr361Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0027 in 1,614,078 control chromosomes in the GnomAD database, including 10 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. T361M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (10 hom.)
• Consequence: NCF2 NM_000433.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 3.96

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012038171).
• BP6: Variant 1-183563531-T-A is Benign according to our data. Variant chr1-183563531-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 466297.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=3}. Variant chr1-183563531-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00171 (261/152242) while in subpopulation AMR AF= 0.00366 (56/15284). AF 95% confidence interval is 0.0029. There are 0 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF2	NM_000433.4	c.1081A>T	p.Thr361Ser	missense_variant	12/15	ENST00000367535.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF2	ENST00000367535.8	c.1081A>T	p.Thr361Ser	missense_variant	12/15	1	NM_000433.4	P1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00192 AC: 481 AN: 251066 Hom.: 0 AF XY: 0.00212 AC XY: 287 AN XY: 135682

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00280 AC: 4089 AN: 1461836 Hom.: 10 Cov.: 32 AF XY: 0.00275 AC XY: 1997 AN XY: 727226

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00231

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00322

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74446

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00257

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00175

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00187 AC: 227

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Dec 08, 2021	NCF2 NM_000433.3 exon 12 p.Thr361Ser (c.1081A>T): This variant has been reported in the literature in at least one individual with inflammatory bowel disease (Denson 2018 PMID:29454792). This variant is also present in 0.2% (333/128812) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-183532666-T-A) and is present in ClinVar (Variation ID:466297). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 25, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29454792) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 01, 2022

Variant summary: NCF2 c.1081A>T (p.Thr361Ser) results in a conservative amino acid change located in the PB1 domain (IPR000270) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251066 control chromosomes (gnomAD), predominantly at a frequency of 0.0027 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in NCF2 causing Chronic Granulomatous Disease (0.00061), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1081A>T has been reported in the literature in at least one heterozygous individual affected with inflammatory bowel disease without strong evidence for causality (Denson_2018). This report does not provide unequivocal conclusions about association of the variant with Chronic Granulomatous Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (benign n=1, likely benign n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.72	T;T;.;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.012	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.011	D;D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;.;.
Polyphen		1.0	.;.;D;D;.;.
Vest4		0.44
MVP		0.56
MPC		0.97
ClinPred		0.026	T
GERP RS		4.6
Varity_R		0.80
gMVP		0.51

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: rs147744729; hg19: chr1-183532666; COSMIC: COSV99055727;