ClinVar Genomic variation as it relates to human health
NM_017802.4(DNAAF5):c.1499G>T (p.Cys500Phe)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(1); Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017802.4(DNAAF5):c.1499G>T (p.Cys500Phe)
Variation ID: 410302 Accession: VCV000410302.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.3 7: 761781 (GRCh38) [ NCBI UCSC ] 7: 801418 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 26, 2018 May 1, 2024 Dec 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017802.4:c.1499G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060272.3:p.Cys500Phe missense NR_075098.2:n.1459G>T non-coding transcript variant NC_000007.14:g.761781G>T NC_000007.13:g.801418G>T NG_033137.1:g.40081G>T - Protein change
- C500F
- Other names
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- Canonical SPDI
- NC_000007.14:761780:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00014
Exome Aggregation Consortium (ExAC) 0.00017
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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DNAAF5 | - | - |
GRCh38 GRCh37 |
526 | 730 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 8, 2023 | RCV000463290.9 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Dec 14, 2023 | RCV000764723.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2023 | RCV003235226.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 18
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895858.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Jun 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003932961.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Identified with a second variant (phase unknown) in individuals with primary ciliary dyskinesia referred for genetic testing at GeneDx and in published literature (Paff et … (more)
Identified with a second variant (phase unknown) in individuals with primary ciliary dyskinesia referred for genetic testing at GeneDx and in published literature (Paff et al., 2018); Published functional studies in mice demonstrate a damaging effect which results in cilia defects, reduced cilia motility, and developmental abnormalities (Horani et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29358401, 36712068, 29363216) (less)
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Likely pathogenic
(Jul 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 18
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175456.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The DNAAF5 c.1499G>T variant is classified as Likely Pathogenic (PM2, PM3, PP1_Supporting, PS3_Supporting) The DNAAF5 c.1499G>T variant is a single nucleotide change in exon 7/13 … (more)
The DNAAF5 c.1499G>T variant is classified as Likely Pathogenic (PM2, PM3, PP1_Supporting, PS3_Supporting) The DNAAF5 c.1499G>T variant is a single nucleotide change in exon 7/13 of the DNAAF5 gene, which is predicted to change the amino acid cysteine at position 500 in the protein to phenylalanine. The variant is rare in population databases (gnomAD allele frequency = 0.011%; 18 het and 0 hom in 152,244 sequenced alleles) (PM2). The variant has been reported in dbSNP (rs144405450), the HGMD database as disease causing (CM184879) and with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 410302). It has been reported in the literature in a pair of siblings with PCD who also harboured a DNAAF5 frameshift variant, however the phase was not specified (PMID: 29363216). The variant has been reported in the homozygous state in two siblings affected by PCD (PMID: 29358401) (PM3, PP1_Supporting). The homozygous siblings both showed mild sinusitis, mild otitis media and absent inner/outer dynein arms on TEM. The proband also presented with situs inversus. Functional studies by the authors using patients' nasal epithelial cells showed a detrimental effect on protein function (PS3_Supporting). (less)
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Likely pathogenic
(Dec 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 18
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV004239031.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
This DNAAF5 missense variant has been reported in the compound heterozygous and homozygous states in individuals with primary ciliary dyskinesia, and has also been shown … (more)
This DNAAF5 missense variant has been reported in the compound heterozygous and homozygous states in individuals with primary ciliary dyskinesia, and has also been shown to segregate with disease . It (rs144405450) is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 319/1608784 total alleles; 0.02%; no homozygotes), and has been reported in ClinVar (Variation ID 410302). Two bioinformatic tools queried predict that this substitution would be damaging, and the cysteine residue at this position is evolutionarily conserved across all of the species assessed. Additionally, functional studies support the prediction that this variant is deleterious, although these findings are insufficient to make a conclusion at this time. We consider c.1499G>T in DNAAF5 to be likely pathogenic. (less)
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Pathogenic
(Oct 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000550928.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 500 of the DNAAF5 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 500 of the DNAAF5 protein (p.Cys500Phe). This variant is present in population databases (rs144405450, gnomAD 0.02%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 29358401, 29363216). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410302). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DNAAF5 function (PMID: 29358401). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Sep 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002702283.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.C500F variant (also known as c.1499G>T), located in coding exon 7 of the DNAAF5 gene, results from a G to T substitution at nucleotide … (more)
The p.C500F variant (also known as c.1499G>T), located in coding exon 7 of the DNAAF5 gene, results from a G to T substitution at nucleotide position 1499. The cysteine at codon 500 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been described homozygous in a pair of siblings with primary ciliary dyskinesia as well as two siblings in a second family in conjunction with a frameshift mutation, but phase was not specified in the latter (Horani A et al. Proc. Natl. Acad. Sci. U.S.A., 2018 02;115:E1221-E1228; Paff T et al. Hum. Mutat., 2018 05;39:653-665). In addition, functional studies of the p.C500F homozygous patients' nasal epithelial cells showed increased HEATR2-SPAG1 protein aggregates as well as misfolded proteins involved in the preassembly complex, which the authors suggest could cause instability; however; information on the sequencing of other involved genes were not available (Horani A et al. Proc. Natl. Acad. Sci. U.S.A., 2018 02;115:E1221-E1228). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Sep 12, 2019)
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no assertion criteria provided
Method: literature only
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CILIARY DYSKINESIA, PRIMARY, 18
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000992449.1
First in ClinVar: Sep 16, 2019 Last updated: Sep 16, 2019 |
Comment on evidence:
For discussion of the c.1499G-T transversion (c.1499G-T, NG_033137.1) in the DNAAF5 gene that was found in compound heterozygous state in 2 Dutch sibs with primary … (more)
For discussion of the c.1499G-T transversion (c.1499G-T, NG_033137.1) in the DNAAF5 gene that was found in compound heterozygous state in 2 Dutch sibs with primary ciliary dyskinesia-18 (CILD18; 614874) by Paff et al. (2018), see 614864.0002. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The effect of Dnaaf5 gene dosage on primary ciliary dyskinesia phenotypes. | Horani A | JCI insight | 2023 | PMID: 37104040 |
Diagnostic yield of a targeted gene panel in primary ciliary dyskinesia patients. | Paff T | Human mutation | 2018 | PMID: 29363216 |
Establishment of the early cilia preassembly protein complex during motile ciliogenesis. | Horani A | Proceedings of the National Academy of Sciences of the United States of America | 2018 | PMID: 29358401 |
Text-mined citations for rs144405450 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.