rs373251065
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_ModerateBP6BP7BS1
The NM_018139.3(DNAAF2):c.423C>T(p.Val141=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,605,600 control chromosomes in the GnomAD database, including 1 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: 𝑓 0.00058 ( 0 hom., cov: 35)
Exomes 𝑓: 0.0011 ( 1 hom. )
Consequence
DNAAF2
NM_018139.3 synonymous
NM_018139.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0910
Genes affected
DNAAF2 (HGNC:20188): (dynein axonemal assembly factor 2) This gene encodes a highly conserved protein involved in the preassembly of dynein arm complexes which power cilia. These complexes are found in some cilia and are assembled in the cytoplasm prior to transport for cilia formation. Mutations in this gene have been associated with primary ciliary dyskinesia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
?
Variant 14-49634727-G-A is Benign according to our data. Variant chr14-49634727-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227314.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
BP7
?
Synonymous conserved (PhyloP=0.091 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000584 (89/152368) while in subpopulation NFE AF= 0.000882 (60/68032). AF 95% confidence interval is 0.000703. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAAF2 | NM_018139.3 | c.423C>T | p.Val141= | synonymous_variant | 1/3 | ENST00000298292.13 | |
DNAAF2 | NM_001083908.2 | c.423C>T | p.Val141= | synonymous_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF2 | ENST00000298292.13 | c.423C>T | p.Val141= | synonymous_variant | 1/3 | 1 | NM_018139.3 | P2 | |
DNAAF2 | ENST00000406043.3 | c.423C>T | p.Val141= | synonymous_variant | 1/2 | 1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000585 AC: 89AN: 152250Hom.: 0 Cov.: 35
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GnomAD3 exomes AF: 0.000782 AC: 181AN: 231512Hom.: 0 AF XY: 0.000774 AC XY: 99AN XY: 127948
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GnomAD4 exome AF: 0.00111 AC: 1616AN: 1453232Hom.: 1 Cov.: 98 AF XY: 0.00109 AC XY: 790AN XY: 723268
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GnomAD4 genome ? AF: 0.000584 AC: 89AN: 152368Hom.: 0 Cov.: 35 AF XY: 0.000550 AC XY: 41AN XY: 74508
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 26, 2015 | This alteration is classified as likely 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. - |
Primary ciliary dyskinesia 10 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 11, 2015 | p.Val141Val in exon 1 of DNAAF2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.1% (72/51640) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs373251065). - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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