rs199776339
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_018076.5(ODAD2):c.1386+4A>G 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 0.0000795 in 1,609,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000082 ( 0 hom. )
Consequence
ODAD2
NM_018076.5 splice_donor_region, intron
NM_018076.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.5457
2
Clinical Significance
Conservation
PhyloP100: 1.68
Genes affected
ODAD2 (HGNC:25583): (outer dynein arm docking complex subunit 2) The protein encoded by this gene contains ten Armadillo repeat motifs (ARMs) and one HEAT repeat, and is thought to be involved in ciliary and flagellar movement. This protein has been shown to localize to the ciliary axonemes and at the ciliary base of respiratory cells. Studies indicate that mutations in this gene cause partial outer dynein arm (ODA) defects in respiratory cilia. The cilia of cells with mutations in this gene displayed either reduced ciliary beat frequency and amplitude, or, complete immotility. Some individuals with primary ciliary dyskensia (PCD) have been shown to have mutations in this gene. PCD is characterized by chronic airway disease and left/right body asymmetry defects. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.34).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000591 (9/152350) while in subpopulation SAS AF= 0.00124 (6/4830). AF 95% confidence interval is 0.000541. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ODAD2 | NM_018076.5 | c.1386+4A>G | splice_donor_region_variant, intron_variant | ENST00000305242.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ODAD2 | ENST00000305242.10 | c.1386+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_018076.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152232Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000108 AC: 27AN: 249358Hom.: 0 AF XY: 0.000104 AC XY: 14AN XY: 134692
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GnomAD4 exome AF: 0.0000816 AC: 119AN: 1457546Hom.: 0 Cov.: 29 AF XY: 0.0000924 AC XY: 67AN XY: 725008
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152350Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74498
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 23 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2020 | This sequence change falls in intron 10 of the ARMC4 mRNA. It does not directly change the encoded amino acid sequence of the ARMC4 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs199776339, ExAC 0.01%). This variant has not been reported in the literature in individuals with ARMC4-related disease. ClinVar contains an entry for this variant (Variation ID: 412241). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098) but according to multiple splice site algorithms this particular variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published functional studies. In summary, this is a rare intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at