chr7-74779322-A-G

Variant names:

• chr7-74779322-A-G
• rs10614
• NM_000265.7:c.295A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000265.7(NCF1):​c.295A>G​(p.Ser99Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,400,968 control chromosomes in the GnomAD database, including 13,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (1794 hom., cov: 22)
  • Exomes 𝑓: 0.11 (13412 hom.)
  • Failed GnomAD Quality Control
• Consequence: NCF1 NM_000265.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.480
• Publications: 22 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001658678).
• BP6: Variant 7-74779322-A-G is Benign according to our data. Variant chr7-74779322-A-G is described in ClinVar as [Benign]. Clinvar id is 2786565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 13412 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF1	NM_000265.7	c.295A>G	p.Ser99Gly	missense_variant	Exon 4 of 11	ENST00000289473.11	NP_000256.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF1	ENST00000289473.11	c.295A>G	p.Ser99Gly	missense_variant	Exon 4 of 11	1	NM_000265.7	ENSP00000289473.4

Frequencies

GnomAD3 genomes AF: 0.171 AC: 23536 AN: 137296 Hom.: 1788 Cov.: 22

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.181

GnomAD4 exome AF: 0.114 AC: 159768 AN: 1400968 Hom.: 13412 Cov.: 32 AF XY: 0.114 AC XY: 79430 AN XY: 697546

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.276 AC: 7305 AN: 26432

American (AMR) AF: 0.137 AC: 5804 AN: 42340

Ashkenazi Jewish (ASJ) AF: 0.0966 AC: 2404 AN: 24882

East Asian (EAS) AF: 0.144 AC: 5333 AN: 37042

South Asian (SAS) AF: 0.120 AC: 9871 AN: 82122

European-Finnish (FIN) AF: 0.145 AC: 7527 AN: 51950

Middle Eastern (MID) AF: 0.181 AC: 931 AN: 5144

European-Non Finnish (NFE) AF: 0.105 AC: 112826 AN: 1073634

Other (OTH) AF: 0.135 AC: 7767 AN: 57422

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.172 AC: 23572 AN: 137406 Hom.: 1794 Cov.: 22 AF XY: 0.173 AC XY: 11572 AN XY: 66968

African (AFR) AF: 0.294 AC: 9804 AN: 33326

American (AMR) AF: 0.179 AC: 2491 AN: 13896

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 378 AN: 3338

East Asian (EAS) AF: 0.134 AC: 589 AN: 4402

South Asian (SAS) AF: 0.116 AC: 494 AN: 4256

European-Finnish (FIN) AF: 0.153 AC: 1502 AN: 9822

Middle Eastern (MID) AF: 0.175 AC: 48 AN: 274

European-Non Finnish (NFE) AF: 0.118 AC: 7701 AN: 65332

Other (OTH) AF: 0.180 AC: 341 AN: 1894

Alfa AF: 0.183 Hom.: 465

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.0
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0017	T
PhyloP100		0.48
Sift4G	Benign	0.52	T
Vest4		0.19
gMVP		0.17

Splicing

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

Other links and lift over

dbSNP: rs10614; hg19: chr7-74193668;