rs748404959
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_017802.4(DNAAF5):c.1231G>A(p.Asp411Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000604 in 1,606,986 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000065 ( 2 hom. )
Consequence
DNAAF5
NM_017802.4 missense
NM_017802.4 missense
Scores
2
11
5
Clinical Significance
Conservation
PhyloP100: 9.14
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 Likely_benign. Variant got -3 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.788
BS2
?
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAAF5 | NM_017802.4 | c.1231G>A | p.Asp411Asn | missense_variant | 5/13 | ENST00000297440.11 | |
DNAAF5 | XM_024446813.2 | c.1231G>A | p.Asp411Asn | missense_variant | 5/12 | ||
DNAAF5 | NR_075098.2 | n.1191G>A | non_coding_transcript_exon_variant | 5/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF5 | ENST00000297440.11 | c.1231G>A | p.Asp411Asn | missense_variant | 5/13 | 1 | NM_017802.4 | P1 | |
DNAAF5 | ENST00000440747.5 | c.637G>A | p.Asp213Asn | missense_variant | 5/13 | 2 | |||
DNAAF5 | ENST00000437419.5 | c.550G>A | p.Asp184Asn | missense_variant | 4/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000610 AC: 15AN: 245846Hom.: 1 AF XY: 0.0000823 AC XY: 11AN XY: 133580
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GnomAD4 exome AF: 0.0000646 AC: 94AN: 1454768Hom.: 2 Cov.: 32 AF XY: 0.0000720 AC XY: 52AN XY: 722418
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
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 | Jul 29, 2023 | 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: 241194). 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. This variant is present in population databases (rs748404959, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 411 of the DNAAF5 protein (p.Asp411Asn). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 18, 2023 | The c.1231G>A (p.D411N) alteration is located in exon 5 (coding exon 5) of the DNAAF5 gene. This alteration results from a G to A substitution at nucleotide position 1231, causing the aspartic acid (D) at amino acid position 411 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
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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