rs797045086
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001277115.2(DNAH11):c.7508_7509insTTG(p.Gly2503_Lys2504insTer) variant causes a stop gained, disruptive inframe insertion change. The variant allele was found at a frequency of 0.000000684 in 1,461,518 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: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
DNAH11
NM_001277115.2 stop_gained, disruptive_inframe_insertion
NM_001277115.2 stop_gained, disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.02
Genes affected
DNAH11 (HGNC:2942): (dynein axonemal heavy chain 11) This gene encodes a ciliary outer dynein arm protein and is a member of the dynein heavy chain family. It is a microtubule-dependent motor ATPase and has been reported to be involved in the movement of respiratory cilia. Mutations in this gene have been implicated in causing Kartagener Syndrome (a combination of situs inversus totalis and Primary Ciliary Dyskinesia (PCD), also called Immotile Cilia Syndrome 1 (ICS1)) and male sterility. [provided by RefSeq, Mar 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 7-21735706-G-GGTT is Pathogenic according to our data. Variant chr7-21735706-G-GGTT is described in ClinVar as [Pathogenic]. Clinvar id is 208573.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DNAH11 | ENST00000409508.8 | c.7508_7509insTTG | p.Gly2503_Lys2504insTer | stop_gained, disruptive_inframe_insertion | 46/82 | 5 | NM_001277115.2 | ENSP00000475939.1 | ||
| DNAH11 | ENST00000605912.1 | c.68_69insTTG | p.Gly23_Lys24insTer | stop_gained, disruptive_inframe_insertion | 1/4 | 3 | ENSP00000476068.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461518Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727016
GnomAD4 exome
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32
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727016
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 7 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 21, 2015 | The p.Lys2504X variant in DNAH11 has not been previously reported in individuals with primary ciliary dyskinesia (PCD) and was absent from large population studies. This variant is an insertion of 3 bases and introduces a nonsense variant which leads to a premature termination codon at position 2504. This variant is predicted to lead to a truncated or absent protein. Complete loss of DNAH11 function is an established disease mechanism in PCD. In summary, this variant meets our criteria to be classified as pathogenic for PCD in an autosomal recessive manner based on the predicted impact of the variant. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at