chr9-34514527-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_012144.4(DNAI1):āc.1703G>Cā(p.Trp568Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,002 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_012144.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNAI1 | NM_012144.4 | c.1703G>C | p.Trp568Ser | missense_variant | Exon 17 of 20 | ENST00000242317.9 | NP_036276.1 | |
DNAI1 | NM_001281428.2 | c.1715G>C | p.Trp572Ser | missense_variant | Exon 17 of 20 | NP_001268357.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251228Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135790
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461882Hom.: 1 Cov.: 32 AF XY: 0.0000275 AC XY: 20AN XY: 727242
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74314
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:2
The p.W568S variant (also known as c.1703G>C), located in coding exon 17 of the DNAI1 gene, results from a G to C substitution at nucleotide position 1703. The tryptophan at codon 568 is replaced by serine, an amino acid with highly dissimilar properties. This variant was first described in two siblings with respiratory distress syndrome, outer dynein arm defects on electron microscopy, and a second pathogenic alteration confirmed in trans; one of the siblings also had situs inversus (Zariwala M et al. Am. J. Respir. Cell Mol. Biol., 2001 Nov;25:577-83). This variant was also detected in another individual with a clinical diagnosis of primary ciliary dyskinesia with outer arm defects on electron microscopy, in compound heterozygous state with a second DNAI1 alteration (Failly M et al. Respiration, 2008 Apr;76:198-204). This amino acid position is highly conserved in available vertebrate species. Based on data from ExAC, the C allele has an overall frequency of approximately <0.01% (1/106200). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 568 of the DNAI1 protein (p.Trp568Ser). This variant is present in population databases (rs772686744, gnomAD 0.004%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 11713099, 18434704; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 288744). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNAI1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17534128, 11713099, 18434704) -
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Kartagener syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at