rs145680314
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_178452.6(DNAAF1):c.1354C>A(p.Pro452Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,612,856 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_178452.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNAAF1 | NM_178452.6 | c.1354C>A | p.Pro452Thr | missense_variant | Exon 8 of 12 | ENST00000378553.10 | NP_848547.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DNAAF1 | ENST00000378553.10 | c.1354C>A | p.Pro452Thr | missense_variant | Exon 8 of 12 | 1 | NM_178452.6 | ENSP00000367815.5 | ||
DNAAF1 | ENST00000563818.5 | n.1031C>A | non_coding_transcript_exon_variant | Exon 4 of 8 | 2 | |||||
DNAAF1 | ENST00000570298.5 | n.1508C>A | non_coding_transcript_exon_variant | Exon 8 of 11 | 2 | |||||
DNAAF1 | ENST00000563093.5 | n.1226-60C>A | intron_variant | Intron 8 of 10 | 2 | ENSP00000457373.1 |
Frequencies
GnomAD3 genomes AF: 0.000811 AC: 123AN: 151722Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000761 AC: 191AN: 250984Hom.: 1 AF XY: 0.000854 AC XY: 116AN XY: 135758
GnomAD4 exome AF: 0.00137 AC: 1995AN: 1461020Hom.: 1 Cov.: 95 AF XY: 0.00135 AC XY: 978AN XY: 726860
GnomAD4 genome AF: 0.000810 AC: 123AN: 151836Hom.: 0 Cov.: 31 AF XY: 0.000714 AC XY: 53AN XY: 74246
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:3
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 452 of the DNAAF1 protein (p.Pro452Thr). This variant is present in population databases (rs145680314, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with DNAAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 216831). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
The p.P452T variant (also known as c.1354C>A), located in coding exon 8 of the DNAAF1 gene, results from a C to A substitution at nucleotide position 1354. The proline at codon 452 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is well conserved on very limited sequence alignment. 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. -
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Primary ciliary dyskinesia 13 Uncertain:1Benign:1
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The p.Pro452Thr variant in DNAAF1 has not been previously reported in individuals with primary ciliary dyskinesia but has been reported in ClinVar (Variation ID 216831). It has also been identified in 0.13% (171/128786) of European chromosomes and in 0.15% (16/10346) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4. -
not provided Uncertain:1
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
DNAAF1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at