rs375053470
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001369.3(DNAH5):c.7915C>T(p.Arg2639Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000112 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
DNAH5
NM_001369.3 stop_gained
NM_001369.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.36
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 5-13794031-G-A is Pathogenic according to our data. Variant chr5-13794031-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 520775.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.7915C>T | p.Arg2639Ter | stop_gained | 48/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.7915C>T | p.Arg2639Ter | stop_gained | 48/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.7870C>T | p.Arg2624Ter | stop_gained | 48/79 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151948Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251098Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135706
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461726Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727166
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
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 | Dec 22, 2023 | This sequence change creates a premature translational stop signal (p.Arg2639*) 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 (rs375053470, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 11788826; Invitae). ClinVar contains an entry for this variant (Variation ID: 520775). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 17, 2021 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Aug 01, 2018 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at