14-49633668-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_018139.3(DNAAF2):ā€‹c.1482A>Gā€‹(p.Thr494Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,610,450 control chromosomes in the GnomAD database, including 423,723 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.65 ( 33831 hom., cov: 32)
Exomes š‘“: 0.72 ( 389892 hom. )

Consequence

DNAAF2
NM_018139.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.79
Variant links:
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 Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 14-49633668-T-C is Benign according to our data. Variant chr14-49633668-T-C is described in ClinVar as [Benign]. Clinvar id is 95892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-49633668-T-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-2.79 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAAF2NM_018139.3 linkuse as main transcriptc.1482A>G p.Thr494Thr synonymous_variant 1/3 ENST00000298292.13 NP_060609.2 Q9NVR5-1
DNAAF2NM_001083908.2 linkuse as main transcriptc.1482A>G p.Thr494Thr synonymous_variant 1/2 NP_001077377.1 Q9NVR5-2
DNAAF2NM_001378453.1 linkuse as main transcriptc.-390A>G 5_prime_UTR_variant 1/2 NP_001365382.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAAF2ENST00000298292.13 linkuse as main transcriptc.1482A>G p.Thr494Thr synonymous_variant 1/31 NM_018139.3 ENSP00000298292.8 Q9NVR5-1
DNAAF2ENST00000406043.3 linkuse as main transcriptc.1482A>G p.Thr494Thr synonymous_variant 1/21 ENSP00000384862.3 Q9NVR5-2

Frequencies

GnomAD3 genomes
AF:
0.648
AC:
98327
AN:
151856
Hom.:
33816
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.483
Gnomad AMI
AF:
0.828
Gnomad AMR
AF:
0.661
Gnomad ASJ
AF:
0.712
Gnomad EAS
AF:
0.149
Gnomad SAS
AF:
0.534
Gnomad FIN
AF:
0.795
Gnomad MID
AF:
0.696
Gnomad NFE
AF:
0.761
Gnomad OTH
AF:
0.670
GnomAD3 exomes
AF:
0.648
AC:
161163
AN:
248550
Hom.:
55997
AF XY:
0.652
AC XY:
87965
AN XY:
134842
show subpopulations
Gnomad AFR exome
AF:
0.471
Gnomad AMR exome
AF:
0.601
Gnomad ASJ exome
AF:
0.717
Gnomad EAS exome
AF:
0.153
Gnomad SAS exome
AF:
0.548
Gnomad FIN exome
AF:
0.780
Gnomad NFE exome
AF:
0.763
Gnomad OTH exome
AF:
0.689
GnomAD4 exome
AF:
0.720
AC:
1050070
AN:
1458478
Hom.:
389892
Cov.:
91
AF XY:
0.716
AC XY:
519182
AN XY:
725110
show subpopulations
Gnomad4 AFR exome
AF:
0.472
Gnomad4 AMR exome
AF:
0.611
Gnomad4 ASJ exome
AF:
0.720
Gnomad4 EAS exome
AF:
0.122
Gnomad4 SAS exome
AF:
0.547
Gnomad4 FIN exome
AF:
0.775
Gnomad4 NFE exome
AF:
0.767
Gnomad4 OTH exome
AF:
0.679
GnomAD4 genome
AF:
0.647
AC:
98395
AN:
151972
Hom.:
33831
Cov.:
32
AF XY:
0.645
AC XY:
47934
AN XY:
74294
show subpopulations
Gnomad4 AFR
AF:
0.483
Gnomad4 AMR
AF:
0.661
Gnomad4 ASJ
AF:
0.712
Gnomad4 EAS
AF:
0.149
Gnomad4 SAS
AF:
0.533
Gnomad4 FIN
AF:
0.795
Gnomad4 NFE
AF:
0.761
Gnomad4 OTH
AF:
0.670
Alfa
AF:
0.724
Hom.:
19885
Bravo
AF:
0.629
Asia WGS
AF:
0.392
AC:
1362
AN:
3478
EpiCase
AF:
0.755
EpiControl
AF:
0.765

ClinVar

Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 22, 2015- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 21, 2013Thr494Thr in exon 1 of DNAAF2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 48.9% (2153/4402) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2985687). -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Primary ciliary dyskinesia 10 Benign:3
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterSep 21, 2015- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Primary ciliary dyskinesia Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 26, 2014This 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. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxNov 10, 2018- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
2.9
DANN
Benign
0.63
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2985687; hg19: chr14-50100386; COSMIC: COSV53568251; COSMIC: COSV53568251; API