rs902156961
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018139.3(DNAAF2):c.1159_1160insGGGG(p.Glu387GlyfsTer105) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,523,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000058 ( 0 hom. )
Consequence
DNAAF2
NM_018139.3 frameshift
NM_018139.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.153
Genes affected
DNAAF2 (HGNC:20188): (dynein axonemal assembly factor 2) This gene encodes a highly conserved protein involved in the preassembly of dynein arm complexes which power cilia. These complexes are found in some cilia and are assembled in the cytoplasm prior to transport for cilia formation. Mutations in this gene have been associated with primary ciliary dyskinesia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-49633990-T-TCCCC is Pathogenic according to our data. Variant chr14-49633990-T-TCCCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 411172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAAF2 | NM_018139.3 | c.1159_1160insGGGG | p.Glu387GlyfsTer105 | frameshift_variant | 1/3 | ENST00000298292.13 | |
DNAAF2 | NM_001083908.2 | c.1159_1160insGGGG | p.Glu387GlyfsTer105 | frameshift_variant | 1/2 | ||
DNAAF2 | NM_001378453.1 | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF2 | ENST00000298292.13 | c.1159_1160insGGGG | p.Glu387GlyfsTer105 | frameshift_variant | 1/3 | 1 | NM_018139.3 | P2 | |
DNAAF2 | ENST00000406043.3 | c.1159_1160insGGGG | p.Glu387GlyfsTer105 | frameshift_variant | 1/2 | 1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 151998Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000846 AC: 1AN: 118240Hom.: 0 AF XY: 0.0000154 AC XY: 1AN XY: 64924
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GnomAD4 exome AF: 0.00000583 AC: 8AN: 1371396Hom.: 0 Cov.: 89 AF XY: 0.00000887 AC XY: 6AN XY: 676340
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GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 151998Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4AN XY: 74250
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 10 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 03, 2023 | - - |
Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 411172). This variant has not been reported in the literature in individuals affected with DNAAF2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Glu387Glyfs*105) in the DNAAF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAAF2 are known to be pathogenic (PMID: 19052621, 24498942). - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at