rs1060501459
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001369.3(DNAH5):c.8025_8026insTA(p.Val2676Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
DNAH5
NM_001369.3 frameshift
NM_001369.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0150
Genes affected
DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [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 5-13793713-C-CTA is Pathogenic according to our data. Variant chr5-13793713-C-CTA is described in ClinVar as [Pathogenic]. Clinvar id is 407233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.8025_8026insTA | p.Val2676Ter | frameshift_variant | 49/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.8025_8026insTA | p.Val2676Ter | frameshift_variant | 49/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.7980_7981insTA | p.Val2661Ter | frameshift_variant | 49/79 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250818Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135602
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461774Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727184
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2022 | This variant has not been reported in the literature in individuals affected with DNAH5-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Val2676*) in the DNAH5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). ClinVar contains an entry for this variant (Variation ID: 407233). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2015 | The c.8024_8025dupTA pathogenic mutation, located in coding exon 49 of the DNAH5 gene, results from a duplication of TA at nucleotide position 8024, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Primary ciliary dyskinesia 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 20, 2020 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at