rs876657683
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_012144.4(DNAI1):βc.336delβ(p.Asp114ThrfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. I111I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_012144.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAI1 | NM_012144.4 | c.336del | p.Asp114ThrfsTer14 | frameshift_variant | 5/20 | ENST00000242317.9 | |
DNAI1 | NM_001281428.2 | c.336del | p.Asp114ThrfsTer14 | frameshift_variant | 5/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAI1 | ENST00000242317.9 | c.336del | p.Asp114ThrfsTer14 | frameshift_variant | 5/20 | 1 | NM_012144.4 | ||
DNAI1 | ENST00000614641.4 | c.336del | p.Asp114ThrfsTer14 | frameshift_variant | 5/20 | 5 | P1 | ||
DNAI1 | ENST00000437363.5 | c.303del | p.Asp103ThrfsTer14 | frameshift_variant | 4/9 | 5 | |||
DNAI1 | ENST00000488369.1 | n.452del | non_coding_transcript_exon_variant | 5/9 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461836Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727218
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74294
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change creates a premature translational stop signal (p.Asp114Thrfs*14) in the DNAI1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAI1 are known to be pathogenic (PMID: 16858015, 29363216). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DNAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228334). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 29, 2019 | The c.336delC pathogenic mutation, located in coding exon 5 of the DNAI1 gene, results from a deletion of one nucleotide at nucleotide position 336, causing a translational frameshift with a predicted alternate stop codon (p.D114Tfs*14). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 27, 2016 | The p.Asp114fs variant in DNAI1 has not been previously reported in individuals with primary ciliary dyskinesia or in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 114 and leads to a premature termination codon 14 amino ac ids downstream. This alteration is then predicted to lead to a truncated or abse nt protein. Homozygous and compound heterozygous loss of function variants in D NAI1 have been well documented in individuals with primary ciliary dyskinesia ac ross several studies and are rare in individuals from large population databases . In addition, an animal model study reveals that absence of Dnaic1 in mice lead s to a reduction of mucociliary clearance resulting in chronic rhinosinusitis, which supports loss of funtion as a disease mechanism (Ostrowski 2009). In summa ry, this variant meets our criteria to be classified as pathogenic for primary c iliary dyskinesia in an autosomal recessive manner (http://www.partners.org/per sonalizedmedicine/LMM) based upon its predicted impact on the protein. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at