rs112306225
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000631.5(NCF4):c.254C>A(p.Thr85Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,612,074 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000631.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NCF4 | NM_000631.5 | c.254C>A | p.Thr85Asn | missense_variant | 3/10 | ENST00000248899.11 | |
NCF4-AS1 | NR_147197.1 | n.351+5038G>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NCF4 | ENST00000248899.11 | c.254C>A | p.Thr85Asn | missense_variant | 3/10 | 1 | NM_000631.5 | P1 | |
NCF4-AS1 | ENST00000619915.1 | n.349+5038G>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00352 AC: 535AN: 152158Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00231 AC: 575AN: 248874Hom.: 6 AF XY: 0.00200 AC XY: 269AN XY: 134820
GnomAD4 exome AF: 0.00198 AC: 2892AN: 1459798Hom.: 11 Cov.: 32 AF XY: 0.00184 AC XY: 1334AN XY: 726318
GnomAD4 genome ? AF: 0.00354 AC: 539AN: 152276Hom.: 1 Cov.: 32 AF XY: 0.00363 AC XY: 270AN XY: 74450
ClinVar
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2022 | Variant summary: NCF4 c.254C>A (p.Thr85Asn) results in a non-conservative amino acid change located in the Phox homology domain (IPR001683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 248874 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 9.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in NCF4 causing Chronic Granulomatous Disease phenotype (0.00025), strongly suggesting that the variant is benign. Although reported among polymorphisms and not among hematologically important mutations in a recent mutational update (example, Roos_2021), to our knowledge, no occurrence of c.254C>A in individuals affected with Chronic Granulomatous Disease and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 14, 2016 | - - |
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 11, 2021 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2020 | This variant is associated with the following publications: (PMID: 29454792) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | NCF4: BP4, BS2 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at