rs119103270

Variant names:

• chr7-74777319-G-A
• rs119103270
• NM_000265.7:c.125G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000265.7(NCF1):​c.125G>A​(p.Arg42Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,457,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R42W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: NCF1 NM_000265.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.84
• Publications: 8 publications found

Genes affected

NCF1 (HGNC:7660): (neutrophil cytosolic factor 1) The protein encoded by this gene is a 47 kDa cytosolic subunit of neutrophil NADPH oxidase. This oxidase is a multicomponent enzyme that is activated to produce superoxide anion. Mutations in this gene have been associated with chronic granulomatous disease. [provided by RefSeq, Jul 2008]

NCF1 Gene-Disease associations (from GenCC):

• granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-74777318-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 636577.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-74777319-G-A is Pathogenic according to our data. Variant chr7-74777319-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000265.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF1	NM_000265.7	MANE Select	c.125G>A	p.Arg42Gln	missense	Exon 2 of 11	NP_000256.4	P14598-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF1	ENST00000289473.11	TSL:1 MANE Select	c.125G>A	p.Arg42Gln	missense	Exon 2 of 11	ENSP00000289473.4	P14598-1
	NCF1	ENST00000969823.1		c.125G>A	p.Arg42Gln	missense	Exon 2 of 12	ENSP00000639882.1
	NCF1	ENST00000969822.1		c.125G>A	p.Arg42Gln	missense	Exon 2 of 11	ENSP00000639881.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248912 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1457098 Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11 AN XY: 724772

African (AFR) AF: 0.0000300 AC: 1 AN: 33320

American (AMR) AF: 0.0000224 AC: 1 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39370

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85764

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109250

Other (OTH) AF: 0.0000333 AC: 2 AN: 60092

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000602 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		8.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.91		Gain of helix (P = 0.0325)
MVP		0.92
ClinPred		0.98	D
GERP RS		4.6
PromoterAI		0.0046	Neutral
Varity_R		0.96
gMVP		0.82
Mutation Taster		=46/54	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs119103270; hg19: chr7-74191665;