8-132675492-A-T
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_012472.6(DNAAF11):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000701 in 1,568,516 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )
Consequence
DNAAF11
NM_012472.6 start_lost
NM_012472.6 start_lost
Scores
5
8
3
Clinical Significance
Conservation
PhyloP100: 3.35
Genes affected
DNAAF11 (HGNC:16725): (dynein axonemal assembly factor 11) The protein encoded by this gene contains several leucine-rich repeat domains and appears to be involved in the motility of cilia. Defects in this gene are a cause of primary ciliary dyskinesia-19 (CILD19). Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 4, 11 and 22. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-132675492-A-T is Pathogenic according to our data. Variant chr8-132675492-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540324.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=2}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000901 AC: 2AN: 221990Hom.: 0 AF XY: 0.00000828 AC XY: 1AN XY: 120744
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74332
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 19 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 11, 2023 | This sequence change affects the initiator methionine of the LRRC6 mRNA. The next in-frame methionine is located at codon 121. This variant is present in population databases (rs377278570, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with LRRC6-related conditions. ClinVar contains an entry for this variant (Variation ID: 540324). This variant disrupts a region of the LRRC6 protein in which other variant(s) (p.Ile100Thr) have been determined to be pathogenic (PMID: 27637300). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Primary ciliary dyskinesia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2023 | The p.M1? pathogenic mutation (also known as c.2T>A) is located in coding exon 1 of the LRRC6 gene and results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. However, there is an alternative initiation (or start) codon in other clinically/biologically relevant transcript(s). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 30, 2023 | The DNAAF11 c.2T>A; p.Met1? variant (rs377278570), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 540324). This variant is found in the African/African-American population with an allele frequency of 0.027% (6/22,344 alleles) in the Genome Aggregation Database. Additionally, a downstream truncating variant has been described in an individual with primary ciliary dyskinesia and is considered pathogenic (Tinoco 2023). The p.Met1 variant abolishes the canonical translation initiation site, which is likely to disrupt gene function. Based on available information, this variant is considered to be likely pathogenic. References: Tinoco EM et al. Primary Ciliary Dyskinesia in a Portuguese Bronchiectasis Outpatient Clinic. Genes (Basel). 2023 Feb 21;14(3):541. PMID: 36980814. - |
DNAAF11-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 01, 2023 | The DNAAF11 c.2T>A variant is predicted to disrupt the translation initiation site (Start loss). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.027% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-133687738-A-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
PROVEAN
Uncertain
.;D;D;D
REVEL
Uncertain
Sift
Uncertain
.;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;D;.;.
Vest4
MVP
ClinPred
D
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