rs776738547
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PM4_SupportingBS1_Supporting
The NM_178452.6(DNAAF1):c.2061_2063dup(p.Pro688_Val688insPro) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,613,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00023 ( 0 hom. )
Consequence
DNAAF1
NM_178452.6 inframe_insertion
NM_178452.6 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.134
Genes affected
DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_178452.6. Strenght limited to Supporting due to length of the change: 1aa.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000227 (331/1460978) while in subpopulation SAS AF= 0.000835 (72/86248). AF 95% confidence interval is 0.00068. There are 0 homozygotes in gnomad4_exome. There are 165 alleles in male gnomad4_exome subpopulation. Median coverage is 34. 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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DNAAF1 | NM_178452.6 | c.2061_2063dup | p.Pro688_Val688insPro | inframe_insertion | 11/12 | ENST00000378553.10 | NP_848547.4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DNAAF1 | ENST00000378553.10 | c.2061_2063dup | p.Pro688_Val688insPro | inframe_insertion | 11/12 | 1 | NM_178452.6 | ENSP00000367815 | P1 |
Frequencies
GnomAD3 genomes 0.000105 AC: 16AN: 152096Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000244 AC: 61AN: 250258Hom.: 0 AF XY: 0.000258 AC XY: 35AN XY: 135566
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GnomAD4 exome AF: 0.000227 AC: 331AN: 1460978Hom.: 0 Cov.: 34 AF XY: 0.000227 AC XY: 165AN XY: 726802
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GnomAD4 genome 0.000105 AC: 16AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74280
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
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 | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 02, 2024 | This variant, c.2061_2063dup, results in the insertion of 1 amino acid(s) of the DNAAF1 protein (p.Pro688dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs776738547, gnomAD 0.07%). 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: 320780). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 01, 2022 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 11, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In-frame insertion of 1 amino acid in a non-repeat region - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at