chr19-55160638-ACCTGGAGTC-A
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_001256715.2(DNAAF3):c.1041_1048+1del variant causes a splice donor, coding sequence change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,611,658 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
DNAAF3
NM_001256715.2 splice_donor, coding_sequence
NM_001256715.2 splice_donor, coding_sequence
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.422
Genes affected
DNAAF3 (HGNC:30492): (dynein axonemal assembly factor 3) The protein encoded by this gene is required for the assembly of axonemal inner and outer dynein arms and plays a role in assembling dynein complexes for transport into cilia. Defects in this gene are a cause of primary ciliary dyskinesia type 2 (CILD2). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.08302583 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.9, offset of 0 (no position change), new splice context is: cagGTaagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-55160638-ACCTGGAGTC-A is Pathogenic according to our data. Variant chr19-55160638-ACCTGGAGTC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 454613.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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DNAAF3 | NM_001256715.2 | c.1041_1048+1del | splice_donor_variant, coding_sequence_variant | 9/12 | ENST00000524407.7 | ||
DNAAF3-AS1 | XR_007067344.1 | n.138-402_138-394del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF3 | ENST00000524407.7 | c.1041_1048+1del | splice_donor_variant, coding_sequence_variant | 9/12 | 1 | NM_001256715.2 | A2 | ||
DNAAF3-AS1 | ENST00000591665.1 | n.968-402_968-394del | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.000166 AC: 25AN: 150450Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 247704Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134530
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461208Hom.: 0 AF XY: 0.0000179 AC XY: 13AN XY: 726868
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GnomAD4 genome AF: 0.000166 AC: 25AN: 150450Hom.: 0 Cov.: 32 AF XY: 0.000232 AC XY: 17AN XY: 73390
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 03, 2019 | - - |
Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 03, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 454613). This variant is also known as c.1245_1252+1del. This variant has not been reported in the literature in individuals affected with DNAAF3-related conditions. This variant is present in population databases (rs767677564, gnomAD 0.03%). This variant, c.1240_1248del, results in the deletion of 3 amino acid(s) of the DNAAF3 protein (p.Gly414_Pro416del), but otherwise preserves the integrity of the reading frame. - |
DNAAF3-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 05, 2023 | The DNAAF3 c.1245_1252+1del9 variant is predicted to result in a deletion affecting a canonical splice site. This variant is predicted to create a new splice donor site based on available splicing prediction programs (Alamut Visual Plus v1.6.1), however, such computer prediction programs are imperfect. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.029% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-55672006-ACCTGGAGTC-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at