rs201998366
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_017802.4(DNAAF5):āc.1063A>Gā(p.Arg355Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000367 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00037 ( 0 hom., cov: 32)
Exomes š: 0.00037 ( 0 hom. )
Consequence
DNAAF5
NM_017802.4 missense
NM_017802.4 missense
Scores
4
9
5
Clinical Significance
Conservation
PhyloP100: 5.35
Genes affected
DNAAF5 (HGNC:26013): (dynein axonemal assembly factor 5) The protein encoded by this gene is essential for the preassembly or stability of axonemal dynein arms, and is found only in organisms with motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia-18, a disorder characterized by abnormalities of motile cilia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000368 (56/152232) while in subpopulation NFE AF= 0.000529 (36/68012). AF 95% confidence interval is 0.000392. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAAF5 | NM_017802.4 | c.1063A>G | p.Arg355Gly | missense_variant | 5/13 | ENST00000297440.11 | |
DNAAF5 | XM_024446813.2 | c.1063A>G | p.Arg355Gly | missense_variant | 5/12 | ||
DNAAF5 | NR_075098.2 | n.1023A>G | non_coding_transcript_exon_variant | 5/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF5 | ENST00000297440.11 | c.1063A>G | p.Arg355Gly | missense_variant | 5/13 | 1 | NM_017802.4 | P1 | |
DNAAF5 | ENST00000440747.5 | c.469A>G | p.Arg157Gly | missense_variant | 5/13 | 2 | |||
DNAAF5 | ENST00000437419.5 | c.382A>G | p.Arg128Gly | missense_variant | 4/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000368 AC: 56AN: 152114Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000330 AC: 83AN: 251240Hom.: 0 AF XY: 0.000302 AC XY: 41AN XY: 135780
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GnomAD4 exome AF: 0.000367 AC: 536AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.000355 AC XY: 258AN XY: 727228
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GnomAD4 genome ? AF: 0.000368 AC: 56AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74438
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2022 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 355 of the DNAAF5 protein (p.Arg355Gly). This variant is present in population databases (rs201998366, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DNAAF5-related conditions. ClinVar contains an entry for this variant (Variation ID: 454845). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNAAF5 protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2024 | The p.R355G variant (also known as c.1063A>G), located in coding exon 5 of the DNAAF5 gene, results from an A to G substitution at nucleotide position 1063. The arginine at codon 355 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 29, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at