rs761622153
Variant summary
Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5
The NM_001369.3(DNAH5):c.5503C>T(p.Gln1835*) 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
Publications
- primary ciliary dyskinesia 3Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
- primary ciliary dyskinesiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001369.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| DNAH5 | NM_001369.3 | MANE Select | c.5503C>T | p.Gln1835* | stop_gained | Exon 34 of 79 | NP_001360.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| DNAH5 | ENST00000265104.5 | TSL:1 MANE Select | c.5503C>T | p.Gln1835* | stop_gained | Exon 34 of 79 | ENSP00000265104.4 | ||
| DNAH5 | ENST00000681290.1 | c.5458C>T | p.Gln1820* | stop_gained | Exon 34 of 79 | ENSP00000505288.1 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000799 AC: 2AN: 250466 AF XY: 0.00000738 show subpopulations
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461602Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 727102 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 3 Pathogenic:7Uncertain:1
The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000372356 /PMID: 30919572). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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
not provided Pathogenic:1
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.
DNAH5-related disorder Pathogenic:1
The DNAH5 c.5503C>T variant is predicted to result in premature protein termination (p.Gln1835*). This variant has been previously reported in an individual with primary ciliary dyskinesia (Al-Dewik et al. 2019. PubMed ID: 30919572, Supplementary Table 1). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in DNAH5 are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Primary ciliary dyskinesia Uncertain:1
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