rs761622153
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PVS1PM2PP5BS1_Supporting
The NM_001369.3(DNAH5):c.5503C>T(p.Gln1835Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001369.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.5503C>T | p.Gln1835Ter | stop_gained | 34/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.5503C>T | p.Gln1835Ter | stop_gained | 34/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.5458C>T | p.Gln1820Ter | stop_gained | 34/79 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250466Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135506
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461602Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 727102
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 3 Pathogenic:5Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 11, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Feb 25, 2020 | - - |
Pathogenic, criteria provided, single submitter | research | Human Genetics Section, Sidra Medicine | Feb 28, 2024 | Loss of function is a known mechanism of disease in DNAH5 related primary ciliary dyskinesia (MIM#608644). Extremely low frequency in gnomAD population databases (Total allele frequency 0.000007985). ClinVar contains an entry for this variant (Variation ID: 372356). The variant is heterozygous in 4 siblings with primary ciliary dyskinesia. We thus classify the variant as pathogenic - |
Uncertain significance, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Oct 11, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 2016 | The Q1835X variant in the DNAH5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q1835X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret Q1835X as a likely pathogenic variant. - |
Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 13, 2022 | This sequence change creates a premature translational stop signal (p.Gln1835*) 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 (rs761622153, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with a copy number gain of DNAH5 exon 1-50. In all individuals where phase was determined, the p.Gln1835* variant and the exon 1-50 copy number gain were on the same chromosome. As a result, it is unknown which copy of the DNAH5 gene this variant is located in, or how this variant impacts gene function. (Invitae). ClinVar contains an entry for this variant (Variation ID: 372356). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at