rs876657637
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_031427.4(DNAL1):βc.224_230delβ(p.Leu75Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000201 in 1,492,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 32)
Exomes π: 7.5e-7 ( 0 hom. )
Consequence
DNAL1
NM_031427.4 frameshift
NM_031427.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.17
Genes affected
DNAL1 (HGNC:23247): (dynein axonemal light chain 1) This gene encodes an axonemal dynein light chain which functions as a component of the outer dynein arms complex. This complex acts as the molecular motor that provides the force to move cilia in an ATP-dependent manner. The encoded protein is expressed in tissues with motile cilia or flagella and may be involved in the movement of sperm flagella. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jan 2011]
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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
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Variant 14-73671555-ATTATCTT-A is Pathogenic according to our data. Variant chr14-73671555-ATTATCTT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAL1 | NM_031427.4 | c.224_230del | p.Leu75Ter | frameshift_variant | 5/8 | ENST00000553645.7 | |
DNAL1 | NM_001201366.2 | c.107_113del | p.Leu36Ter | frameshift_variant | 6/9 | ||
DNAL1 | XM_017021679.3 | c.107_113del | p.Leu36Ter | frameshift_variant | 6/9 | ||
DNAL1 | XM_024449715.2 | c.107_113del | p.Leu36Ter | frameshift_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAL1 | ENST00000553645.7 | c.224_230del | p.Leu75Ter | frameshift_variant | 5/8 | 1 | NM_031427.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 7.46e-7 AC: 1AN: 1340554Hom.: 0 AF XY: 0.00000151 AC XY: 1AN XY: 663860
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74368
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 16 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 27, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 228252). This variant has not been reported in the literature in individuals affected with DNAL1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu75*) in the DNAL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAL1 are known to be pathogenic (PMID: 21496787). - |
Primary ciliary dyskinesia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 03, 2016 | The p.Leu36X variant in DNAL1 has not been previously reported in individuals wi th pulmonary disease or in large population studies. This variant is a deletion of 7 nucleotides at position 107 and is predicted to alter the protein reading-f rame, resulting in a premature termination codon at amino acid position 36. This alteration is then predicted to lead to a truncated or absent protein. In summa ry, although additional studies are required to fully establish its clinical sig nificance, the p.Leu36X variant is likely pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at