rs727502971
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001369.3(DNAH5):c.13194_13197del(p.Asp4398GlufsTer16) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000149 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D4398D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001369.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.13194_13197del | p.Asp4398GlufsTer16 | frameshift_variant | 76/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.13194_13197del | p.Asp4398GlufsTer16 | frameshift_variant | 76/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.13149_13152del | p.Asp4383GlufsTer16 | frameshift_variant | 76/79 | A1 | |||
DNAH5 | ENST00000683611.1 | n.527_530del | non_coding_transcript_exon_variant | 2/5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251356Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135850
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461872Hom.: 0 AF XY: 0.0000124 AC XY: 9AN XY: 727242
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 08, 2013 | The Asp4398fs variant in DNAH5 has been reported in one individual with PCD and outer dynein arm (ODA) defects who carried a missense variant identified on the other copy of this gene (Hornef 2006). The variant has not been identified in la rge population studies. This frameshift variant is predicted to alter the protei n's amino acid sequence beginning at position 4398 and lead to a premature termi nation codon 16 amino acids downstream. This alteration is then predicted to lea d to a truncated or absent protein. Frameshift and other truncating variants in DNAH5 are associated with autosomal recessive PCD (Hornef 2006). In summary, thi s variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change creates a premature translational stop signal (p.Asp4398Glufs*16) 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 (rs727502971, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16627867, 26373788). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 163134). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at