16-84154770-C-G
Position:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_178452.6(DNAAF1):āc.546C>Gā(p.Asn182Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,614,120 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0015 ( 0 hom., cov: 32)
Exomes š: 0.0020 ( 6 hom. )
Consequence
DNAAF1
NM_178452.6 missense
NM_178452.6 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 1.98
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 Benign. Variant got -11 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.09108555).
BP6
Variant 16-84154770-C-G is Benign according to our data. Variant chr16-84154770-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166997.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00148 (225/152298) while in subpopulation AMR AF= 0.00288 (44/15298). AF 95% confidence interval is 0.0022. There are 0 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 6 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAAF1 | NM_178452.6 | c.546C>G | p.Asn182Lys | missense_variant | 4/12 | ENST00000378553.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF1 | ENST00000378553.10 | c.546C>G | p.Asn182Lys | missense_variant | 4/12 | 1 | NM_178452.6 | P1 | |
DNAAF1 | ENST00000567918.5 | c.546C>G | p.Asn182Lys | missense_variant, NMD_transcript_variant | 4/7 | 1 | |||
DNAAF1 | ENST00000570298.5 | n.700C>G | non_coding_transcript_exon_variant | 4/11 | 2 | ||||
DNAAF1 | ENST00000563093.5 | c.546C>G | p.Asn182Lys | missense_variant, NMD_transcript_variant | 4/11 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00149 AC: 226AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00137 AC: 345AN: 251476Hom.: 0 AF XY: 0.00130 AC XY: 177AN XY: 135910
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GnomAD4 exome AF: 0.00201 AC: 2935AN: 1461822Hom.: 6 Cov.: 32 AF XY: 0.00191 AC XY: 1390AN XY: 727218
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GnomAD4 genome AF: 0.00148 AC: 225AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 117AN XY: 74482
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 17, 2014 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Primary ciliary dyskinesia Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 15, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | Jan 04, 2018 | - - |
Primary ciliary dyskinesia 13 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of ubiquitination at N182 (P = 0.0289);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at