14-49633594-TC-T
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_018139.3(DNAAF2):c.1555del(p.Glu519SerfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,570 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: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
DNAAF2
NM_018139.3 frameshift
NM_018139.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.184
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 12 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 14-49633594-TC-T is Pathogenic according to our data. Variant chr14-49633594-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505384.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAAF2 | NM_018139.3 | c.1555del | p.Glu519SerfsTer16 | frameshift_variant | 1/3 | ENST00000298292.13 | |
DNAAF2 | NM_001083908.2 | c.1555del | p.Glu519SerfsTer16 | frameshift_variant | 1/2 | ||
DNAAF2 | NM_001378453.1 | c.-317del | 5_prime_UTR_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF2 | ENST00000298292.13 | c.1555del | p.Glu519SerfsTer16 | frameshift_variant | 1/3 | 1 | NM_018139.3 | P2 | |
DNAAF2 | ENST00000406043.3 | c.1555del | p.Glu519SerfsTer16 | frameshift_variant | 1/2 | 1 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461570Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727066
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 18, 2016 | The p.Glu519SerfsX16 variant in DNAAF2 has not been previously reported in patie nts and was absent from large population studies. This variant is predicted to c ause a frameshift, which alters the protein?s amino acid sequence beginning at p osition 519 and leads to a premature termination codon 16 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein. Bi allelic loss of function of DNAAF2 has been associated with primary ciliary dysk inesia in a limited number of cases. In summary, although additional studies are required to fully establish the role of this gene in disease and the clinical s ignificance of this variant, the p.Glu519SerfsX16 variant is likely pathogenic f or primary ciliary dyskinesia in an autosomal recessive manner. - |
Computational scores
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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