16-84170123-AGGACGGAGATGGAGAGCCAGAGG-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_178452.6(DNAAF1):c.1300_1322delGGAGATGGAGAGCCAGAGGGGAC(p.Gly434fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,582,856 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 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )
Consequence
DNAAF1
NM_178452.6 frameshift
NM_178452.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.03
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 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 16-84170123-AGGACGGAGATGGAGAGCCAGAGG-A is Pathogenic according to our data. Variant chr16-84170123-AGGACGGAGATGGAGAGCCAGAGG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 525404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNAAF1 | NM_178452.6 | c.1300_1322delGGAGATGGAGAGCCAGAGGGGAC | p.Gly434fs | frameshift_variant | 8/12 | ENST00000378553.10 | NP_848547.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DNAAF1 | ENST00000378553.10 | c.1300_1322delGGAGATGGAGAGCCAGAGGGGAC | p.Gly434fs | frameshift_variant | 8/12 | 1 | NM_178452.6 | ENSP00000367815.5 | ||
DNAAF1 | ENST00000563818.5 | n.977_999delGGAGATGGAGAGCCAGAGGGGAC | non_coding_transcript_exon_variant | 4/8 | 2 | |||||
DNAAF1 | ENST00000570298.5 | n.1454_1476delGGAGATGGAGAGCCAGAGGGGAC | non_coding_transcript_exon_variant | 8/11 | 2 | |||||
DNAAF1 | ENST00000563093.5 | n.1225+75_1226-92delGGAGATGGAGAGCCAGAGGGGAC | intron_variant | 2 | ENSP00000457373.1 |
Frequencies
GnomAD3 genomes AF: 0.0000527 AC: 8AN: 151692Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251330Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135846
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GnomAD4 exome AF: 0.000186 AC: 266AN: 1431164Hom.: 0 AF XY: 0.000166 AC XY: 118AN XY: 711350
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GnomAD4 genome AF: 0.0000527 AC: 8AN: 151692Hom.: 0 Cov.: 32 AF XY: 0.0000675 AC XY: 5AN XY: 74094
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2021 | The c.1300_1322del23 pathogenic mutation, located in coding exon 8 of the DNAAF1 gene, results from a deletion of 23 nucleotides at nucleotide positions 1300 to 1322, causing a translational frameshift with a predicted alternate stop codon (p.G434Pfs*4). This alteration was detected along with another DNAAF1 translational frameshift mutation in an individual with primary ciliary dyskinesia (PCD) (Duquesnoy P et al. Am J Hum Genet, 2009 Dec;85:890-6). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 19, 2023 | This sequence change creates a premature translational stop signal (p.Gly434Profs*4) in the DNAAF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAAF1 are known to be pathogenic (PMID: 19944400, 19944405). This variant is present in population databases (rs745495583, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 19944405). ClinVar contains an entry for this variant (Variation ID: 525404). For these reasons, this variant has been classified as Pathogenic. - |
Primary ciliary dyskinesia 13 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 29, 2023 | - - |
DNAAF1-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 12, 2024 | The DNAAF1 c.1300_1322del23 variant is predicted to result in a frameshift and premature protein termination (p.Gly434Profs*4). This variant has been reported with a second DNAAF1 variant in an individual with primary ciliary dyskinesia (Duquesnoy et al. 2009. PubMed ID: 19944405) and in the heterozygous state in an individual with testicular cancer (Litchfield et al. 2016. PubMed ID: 27996046). At PreventionGenetics, this variant has been detected in the homozygous state in individuals who received testing for ciliopathies (Internal Data). This variant is reported in 0.0062% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in DNAAF1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at