rs147744729

Variant names:

• chr1-183563531-T-A
• rs147744729
• NM_000433.4:c.1081A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Publications: 7 publications found

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]

SMG7 Gene-Disease associations (from GenCC):

• autoimmune disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 466297.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF2	NM_000433.4	c.1081A>T	p.Thr361Ser	missense_variant	Exon 12 of 15	ENST00000367535.8	NP_000424.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF2	ENST00000367535.8	c.1081A>T	p.Thr361Ser	missense_variant	Exon 12 of 15	1	NM_000433.4	ENSP00000356505.4

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

GnomAD2 exomes AF: 0.00192 AC: 481 AN: 251066 AF XY: 0.00212

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 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

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.00190 AC: 85 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00231 AC: 199 AN: 86252

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53418

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5732

European-Non Finnish (NFE) AF: 0.00322 AC: 3585 AN: 1112000

Other (OTH) AF: 0.00277 AC: 167 AN: 60396

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

African (AFR) AF: 0.000481 AC: 20 AN: 41560

American (AMR) AF: 0.00366 AC: 56 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00257 AC: 175 AN: 68006

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

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

May 25, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 08, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 20, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1 Benign:1

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 07, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

not specified Benign:1

Jul 01, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.0	.;.;T;T;T;T
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
MutationAssessor	Benign	0.0	.;.;M;M;.;.
PhyloP100		4.0
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;.;.
Vest4		0.44
ClinPred		0.026	T
GERP RS		4.6
Varity_R		0.80
gMVP		0.51
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

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