rs749731714
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001206927.2(DNAH8):c.7793del(p.Leu2598TrpfsTer61) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,882 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
DNAH8
NM_001206927.2 frameshift
NM_001206927.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.283
Genes affected
DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 6-38875761-GT-G is Pathogenic according to our data. Variant chr6-38875761-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 525331.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH8 | NM_001206927.2 | c.7793del | p.Leu2598TrpfsTer61 | frameshift_variant | 53/93 | ENST00000327475.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH8 | ENST00000327475.11 | c.7793del | p.Leu2598TrpfsTer61 | frameshift_variant | 53/93 | 5 | NM_001206927.2 | P2 | |
DNAH8 | ENST00000359357.7 | c.7142del | p.Leu2381TrpfsTer61 | frameshift_variant | 51/91 | 2 | A2 | ||
DNAH8 | ENST00000449981.6 | c.7793del | p.Leu2598TrpfsTer61 | frameshift_variant | 52/82 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251184Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135756
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461710Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727166
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 12, 2017 | Loss-of-function variants in DNAH8 are known to be pathogenic (PMID: 24307375). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with DNAH8-related disease. This variant is present in population databases (rs749731714, ExAC 0.002%). This sequence change creates a premature translational stop signal (p.Leu2598Trpfs*61) in the DNAH8 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
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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