rs150868941
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001369.3(DNAH5):c.4961G>A(p.Arg1654Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000483 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1654W) has been classified as Likely benign.
Frequency
Consequence
NM_001369.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.4961G>A | p.Arg1654Gln | missense_variant | 31/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.4961G>A | p.Arg1654Gln | missense_variant | 31/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.4916G>A | p.Arg1639Gln | missense_variant | 31/79 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000243 AC: 37AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000270 AC: 68AN: 251396Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135878
GnomAD4 exome AF: 0.000508 AC: 743AN: 1461788Hom.: 0 Cov.: 34 AF XY: 0.000507 AC XY: 369AN XY: 727190
GnomAD4 genome AF: 0.000243 AC: 37AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2016 | The R1654Q variant in the DNAH5 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1654Q variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The R1654Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1654Q as a variant of uncertain significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Primary ciliary dyskinesia Uncertain:2Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 03, 2017 | The p.R1654Q variant (also known as c.4961G>A), located in coding exon 31 of the DNAH5 gene, results from a G to A substitution at nucleotide position 4961. The arginine at codon 1654 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
Primary ciliary dyskinesia 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 05, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at