rs761851970
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_178452.6(DNAAF1):c.694C>G(p.Leu232Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
DNAAF1
NM_178452.6 missense
NM_178452.6 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 1.27
Genes affected
DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.784
PP5
?
Variant 16-84155702-C-G is Pathogenic according to our data. Variant chr16-84155702-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 579235.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAAF1 | NM_178452.6 | c.694C>G | p.Leu232Val | missense_variant | 5/12 | ENST00000378553.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF1 | ENST00000378553.10 | c.694C>G | p.Leu232Val | missense_variant | 5/12 | 1 | NM_178452.6 | P1 | |
DNAAF1 | ENST00000567918.5 | c.694C>G | p.Leu232Val | missense_variant, NMD_transcript_variant | 5/7 | 1 | |||
DNAAF1 | ENST00000570298.5 | n.848C>G | non_coding_transcript_exon_variant | 5/11 | 2 | ||||
DNAAF1 | ENST00000563093.5 | c.694C>G | p.Leu232Val | missense_variant, NMD_transcript_variant | 5/11 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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Cov.:
32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251486Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135914
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727248
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GnomAD4 genome ? Cov.: 32
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32
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 29, 2018 | This sequence change replaces leucine with valine at codon 232 of the DNAAF1 protein (p.Leu232Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs761851970, ExAC 0.003%). This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in DNAAF1 in an individual affected with primary ciliary dyskinesia (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
M
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of methylation at K231 (P = 0.0453);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -1
DS_DL_spliceai
Position offset: 47
Find out detailed SpliceAI scores and Pangolin per-transcript scores at