rs151000177
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1
The NM_001369.3(DNAH5):c.975+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000333 in 1,613,900 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00038 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00033 ( 1 hom. )
Consequence
DNAH5
NM_001369.3 splice_donor_region, intron
NM_001369.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001616
1
Clinical Significance
Conservation
PhyloP100: 1.51
Genes affected
DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP6
?
Variant 5-13919170-G-A is Benign according to our data. Variant chr5-13919170-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 414355.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000381 (58/152276) while in subpopulation EAS AF= 0.0106 (55/5180). AF 95% confidence interval is 0.00838. There are 1 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.975+6C>T | splice_donor_region_variant, intron_variant | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.975+6C>T | splice_donor_region_variant, intron_variant | 1 | NM_001369.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000381 AC: 58AN: 152158Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000518 AC: 130AN: 250848Hom.: 0 AF XY: 0.000494 AC XY: 67AN XY: 135596
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GnomAD4 exome AF: 0.000328 AC: 479AN: 1461624Hom.: 1 Cov.: 32 AF XY: 0.000309 AC XY: 225AN XY: 727130
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GnomAD4 genome ? AF: 0.000381 AC: 58AN: 152276Hom.: 1 Cov.: 32 AF XY: 0.000470 AC XY: 35AN XY: 74466
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 03, 2023 | The DNAH5 c.975+6C>T variant (rs151000177) is reported in an individual with bronchiectasis who carried an additional variant in DNAH5; both variants were classified as uncertain significance (Guan 2018). The c.975+6C>T variant is also reported in ClinVar (Variation ID: 414355). It is observed in the general population with an overall allele frequency of 0.05% (151/282240 alleles) in the Genome Aggregation Database. Computational analyses are conflicting in whether this variant is predicted to alter splicing (Alamut Visual Plus v.1.5.1, SpliceAI). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Guan WJ et al. Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis. 2018 May;10(5):2618-2630. PMID: 29997923. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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. - |
Primary ciliary dyskinesia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at