rs397515540
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001369.3(DNAH5):βc.10815delβ(p.Pro3606HisfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.00019 ( 0 hom., cov: 32)
Exomes π: 0.00043 ( 0 hom. )
Consequence
DNAH5
NM_001369.3 frameshift
NM_001369.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.172
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 5-13753289-GA-G is Pathogenic according to our data. Variant chr5-13753289-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 65636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13753289-GA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DNAH5 | NM_001369.3 | c.10815del | p.Pro3606HisfsTer23 | frameshift_variant | 63/79 | ENST00000265104.5 | NP_001360.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DNAH5 | ENST00000265104.5 | c.10815del | p.Pro3606HisfsTer23 | frameshift_variant | 63/79 | 1 | NM_001369.3 | ENSP00000265104 | P4 | |
| DNAH5 | ENST00000681290.1 | c.10770del | p.Pro3591HisfsTer23 | frameshift_variant | 63/79 | ENSP00000505288 | A1 |
Frequencies
GnomAD3 genomes 0.000191 AC: 29AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000163 AC: 41AN: 250906Hom.: 1 AF XY: 0.000155 AC XY: 21AN XY: 135630
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GnomAD4 exome AF: 0.000434 AC: 635AN: 1461660Hom.: 0 Cov.: 31 AF XY: 0.000417 AC XY: 303AN XY: 727134
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GnomAD4 genome 0.000191 AC: 29AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74316
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:20Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 3 Pathogenic:9Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary ciliary dyskinesia 3, with or without situs inversus (PCD; MIM#608644). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 45 heterozygotes, 1 homozygote). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple families with primary ciliary dyskinesia (ClinVar, LOVD, PMIDs: 29363216, 16627867, 23477994). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 19, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 13, 2020 | PVS1, PM3, PP5 - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 15, 2006 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Mar 26, 2020 | ACMG codes: PVS1, PM3, PP4, PP5 - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 07, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 17, 2016 | The DNAH5 c.10815delT (p.Pro3606HisfsTer23) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Pro3606HisfsTer23 variant has been reported in a total of 17 individuals with primary ciliary dyskinesia, including in two in a homozygous state and in 15 in a compound heterozygous state (Hornef et al. 2006; Djakow et al. 2012; Ferkol et al. 2013; Kim et al. 2014; Raidt et al. 2014). The p.Pro3606HisfsTer23 variant was found to segregate with disease where familial DNA was available, and haplotype analysis revealed this variant is a founder mutation (Hornef et al. 2006). The p.Pro3606HisfsTer23 variant was absent from 70 controls and is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of frameshift variants, the p.Pro3606HisfsTer23 variant is classified as pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Dec 06, 2022 | c.10815delT in DNAH5 has been identified in multiple unrelated individuals as well as families with primary ciliary dyskinesia and is a known North American founder mutation. This frameshift variant (rs397515540) has been reported in ClinVar (Variation ID 65636) and is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 47/282304 total alleles; 0.0167%; 1 homozygote). This frameshift variant results in a premature stop codon in exon 64 of 79, likely leading to nonsense-mediated decay and lack of protein production. We consider c.10815delT; p.Pro3606fs in DNAH5 to be pathogenic. - |
Primary ciliary dyskinesia Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Feb 05, 2024 | This sequence change in DNAH5 is a frameshift variant predicted to cause a premature stop codon, p.(Pro3606Hisfs*23), in biologically relevant exon 64/79 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.05% (638/1,179,900 alleles) in the European (non-Finnish) population. This variant is a North American founder mutation that has been detected in the homozygous and compound heterozygous state in multiple individuals with primary ciliary dyskinesia (PCD), confirmed in trans in at least one individual (PMID: 16627867, 29363216). It segregates with PCD in at least one family (PMID: 16627867). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PP1. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2021 | The c.10815delT pathogenic mutation, located in coding exon 63 of the DNAH5 gene, results from a deletion of one nucleotide at nucleotide position 10815, causing a translational frameshift with a predicted alternate stop codon (p.P3606Hfs*23). In one study, this mutation was seen in 7 of 134 (5.2%) primary ciliary dyskinesia (PCD) families, with a particularly high prevalence in individuals with PCD from the United States (Hornef N et al. Am. J. Respir. Crit. Care Med., 2006 Jul;174:120-6). 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, criteria provided, single submitter | clinical testing | Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre | Dec 11, 2023 | ACMG: PVS1, PM2, PM3, PP5 - |
| Pathogenic, criteria provided, single submitter | research | Centre for Genomic and Experimental Medicine, University of Edinburgh | Apr 01, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | This sequence change creates a premature translational stop signal (p.Pro3606Hisfs*23) 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 (rs397515540, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16627867, 22416021, 23477994, 24498942). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65636). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Aug 01, 2018 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 03, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 20, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24498942, 16627867, 20301301, 28832562, 28991257, 23477994, 22416021, 29453417, 25186273, 31772028, 31879361, 31980526, 32111882, 31589614, 33726816) - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at