rs756032160
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001369.3(DNAH5):c.11653C>T(p.Arg3885Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,862 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 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.11653C>T | p.Arg3885Ter | stop_gained | 68/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.11653C>T | p.Arg3885Ter | stop_gained | 68/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.11608C>T | p.Arg3870Ter | stop_gained | 68/79 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152058Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251222Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135764
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461804Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727214
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74264
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 3 Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 16, 2021 | NM_001369.2(DNAH5):c.11653C>T(R3885*) is a nonsense variant classified as pathogenic in the context of DNAH5-related primary ciliary dyskinesia. R3885* has been observed in cases with relevant disease (PMID: 31213628, 31638833). Functional assessments of this variant are not available in the literature. R3885* has been observed in population frequency databases (gnomAD: ASJ 0.05%). In summary, NM_001369.2(DNAH5):c.11653C>T(R3885*) is a nonsense variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 29, 2017 | The DNAH5 c.11653C>T (p.Arg3885Ter) variant is a stop-gained variant, which was observed by ICSL 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 for this variant, it 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. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for primary ciliary dyskinesia. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | DASA | Nov 03, 2022 | The c.11653C>T;p.(Arg3885*) variant creates a premature translational stop signal in the DNAH5 gene. It is expected to result in an absent or disrupted protein product - PVS1. The variant is present at low allele frequencies population databases (rs756032160 – gnomAD 0.0001973%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is likely pathogenic. - |
Primary ciliary dyskinesia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre | Dec 11, 2023 | ACMG: PVS1, PM2, PM3, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change creates a premature translational stop signal (p.Arg3885*) 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 (rs756032160, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with DNAH5-related conditions. ClinVar contains an entry for this variant (Variation ID: 525218). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at