NM_178452.6:c.1033G>C
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BS1_Supporting
The NM_178452.6(DNAAF1):c.1033G>C(p.Glu345Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_178452.6 missense, splice_region
Scores
Clinical Significance
Conservation
Publications
- primary ciliary dyskinesia 13Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
- primary ciliary dyskinesiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNAAF1 | NM_178452.6 | c.1033G>C | p.Glu345Gln | missense_variant, splice_region_variant | Exon 8 of 12 | ENST00000378553.10 | NP_848547.4 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152268Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000438 AC: 11AN: 251298 AF XY: 0.0000147 show subpopulations
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461318Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 726974 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000197 AC: 30AN: 152386Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17AN XY: 74524 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:2
The p.E345Q variant (also known as c.1033G>C), located in coding exon 8 of the DNAAF1 gene, results from a G to C substitution at nucleotide position 1033. The glutamic acid at codon 345 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in an individual with recurrent respiratory tract infection and severe early-onset obesity. The individual also had c.1698+1G>A in the DNAAF1 gene; however, the phase is unknown (Paz-Filho G et al. Genes (Basel), 2014 Aug;5:709-25). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 345 of the DNAAF1 protein (p.Glu345Gln). This variant is present in population databases (rs538389058, gnomAD 0.06%). This missense change has been observed in individual(s) with recurrent airway infections and severe obesity (PMID: 25158045). ClinVar contains an entry for this variant (Variation ID: 410282). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Primary ciliary dyskinesia 13 Uncertain:1
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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at