chr19-55161292-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_ModeratePM2PP3_StrongPP5
The NM_001256715.2(DNAAF3):c.789+1G>C variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,457,066 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001256715.2 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAAF3 | NM_001256715.2 | c.789+1G>C | splice_donor_variant | ENST00000524407.7 | |||
DNAAF3-AS1 | XR_007067344.1 | n.306+78C>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF3 | ENST00000524407.7 | c.789+1G>C | splice_donor_variant | 1 | NM_001256715.2 | A2 | |||
DNAAF3-AS1 | ENST00000591665.1 | n.1136+78C>G | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 exomes AF: 0.0000577 AC: 14AN: 242814Hom.: 0 AF XY: 0.0000227 AC XY: 3AN XY: 132380
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1457066Hom.: 0 Cov.: 39 AF XY: 0.00000414 AC XY: 3AN XY: 724390
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change affects a donor splice site in intron 7 of the DNAAF3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DNAAF3 are known to be pathogenic (PMID: 22387996). This variant is present in population databases (rs770143722, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DNAAF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 410289). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2022 | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at