NM_018139.3:c.374T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018139.3(DNAAF2):​c.374T>G​(p.Leu125Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,433,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L125P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 35)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DNAAF2
NM_018139.3 missense

Scores

10
4
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.67

Publications

0 publications found
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]
DNAAF2 Gene-Disease associations (from GenCC):
  • primary ciliary dyskinesia 10
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
  • primary ciliary dyskinesia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAAF2NM_018139.3 linkc.374T>G p.Leu125Arg missense_variant Exon 1 of 3 ENST00000298292.13 NP_060609.2 Q9NVR5-1
DNAAF2NM_001083908.2 linkc.374T>G p.Leu125Arg missense_variant Exon 1 of 2 NP_001077377.1 Q9NVR5-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAAF2ENST00000298292.13 linkc.374T>G p.Leu125Arg missense_variant Exon 1 of 3 1 NM_018139.3 ENSP00000298292.8 Q9NVR5-1
DNAAF2ENST00000406043.3 linkc.374T>G p.Leu125Arg missense_variant Exon 1 of 2 1 ENSP00000384862.3 Q9NVR5-2

Frequencies

GnomAD3 genomes
Cov.:
35
GnomAD4 exome
AF:
0.00000140
AC:
2
AN:
1433590
Hom.:
0
Cov.:
98
AF XY:
0.00
AC XY:
0
AN XY:
711894
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33026
American (AMR)
AF:
0.00
AC:
0
AN:
40928
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25660
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38678
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84088
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
43790
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5722
European-Non Finnish (NFE)
AF:
0.00000181
AC:
2
AN:
1102174
Other (OTH)
AF:
0.00
AC:
0
AN:
59524
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.77
T;T
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Benign
-0.81
T
MutationAssessor
Uncertain
2.6
M;M
PhyloP100
3.7
PrimateAI
Uncertain
0.79
T
PROVEAN
Pathogenic
-4.9
D;D
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.82
MutPred
0.74
Gain of catalytic residue at L121 (P = 0.0018);Gain of catalytic residue at L121 (P = 0.0018);
MVP
0.71
MPC
1.7
ClinPred
1.0
D
GERP RS
5.3
PromoterAI
0.0028
Neutral
Varity_R
0.95
gMVP
0.94
Mutation Taster
=47/53
disease causing

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

Other links and lift over

dbSNP: rs771875922; hg19: chr14-50101494; API