rs1474945018
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001369.3(DNAH5):c.6343del(p.Ile2115Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 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: 8.02
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 5-13829610-AT-A is Pathogenic according to our data. Variant chr5-13829610-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 454791.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.6343del | p.Ile2115Ter | frameshift_variant | 38/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.6343del | p.Ile2115Ter | frameshift_variant | 38/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.6298del | p.Ile2100Ter | frameshift_variant | 38/79 | A1 | |||
DNAH5 | ENST00000683090.1 | n.1274del | non_coding_transcript_exon_variant | 3/7 |
Frequencies
GnomAD3 genomes ? Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251290Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135808
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461874Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2AN XY: 727238
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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:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2023 | This sequence change creates a premature translational stop signal (p.Ile2115*) 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). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 25186273). ClinVar contains an entry for this variant (Variation ID: 454791). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 12, 2017 | The c.6343delA pathogenic mutation, located in coding exon 38 of the DNAH5 gene, results from a deletion of one nucleotide at nucleotide position 6343, causing a translational frameshift with a predicted alternate stop codon (p.I2115*). This mutation was identified in an individual with primary ciliary dyskinesia in conjunction with a frameshift alteration; however, the phase of the alterations was not provided (Raidt J et al. Eur. Respir. J., 2014 Dec;44:1579-88). In addition to the clinical data presented in the literature, 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, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 01, 2021 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at