16-84170124-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_178452.6(DNAAF1):​c.1296G>T​(p.Glu432Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E432K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.933

Publications

19 publications found
Variant links:
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]
DNAAF1 Gene-Disease associations (from GenCC):
  • primary ciliary dyskinesia 13
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
  • 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: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04587558).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAAF1NM_178452.6 linkc.1296G>T p.Glu432Asp missense_variant Exon 8 of 12 ENST00000378553.10 NP_848547.4 Q8NEP3-1A0A140VJN4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAAF1ENST00000378553.10 linkc.1296G>T p.Glu432Asp missense_variant Exon 8 of 12 1 NM_178452.6 ENSP00000367815.5 Q8NEP3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251252
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.88e-7
AC:
1
AN:
1454030
Hom.:
0
Cov.:
100
AF XY:
0.00
AC XY:
0
AN XY:
723350
show subpopulations
African (AFR)
AF:
0.0000300
AC:
1
AN:
33296
American (AMR)
AF:
0.00
AC:
0
AN:
44266
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25782
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39566
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86104
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53308
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5582
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1106182
Other (OTH)
AF:
0.00
AC:
0
AN:
59944
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
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
167
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.78
CADD
Benign
0.37
DANN
Benign
0.75
DEOGEN2
Benign
0.0057
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.0024
N
LIST_S2
Benign
0.50
T
M_CAP
Benign
0.0048
T
MetaRNN
Benign
0.046
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.3
L
PhyloP100
-0.93
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.63
N
REVEL
Benign
0.017
Sift
Benign
0.099
T
Sift4G
Benign
0.61
T
Polyphen
0.0
B
Vest4
0.022
MutPred
0.11
Loss of methylation at K430 (P = 0.0922);
MVP
0.16
MPC
0.019
ClinPred
0.036
T
GERP RS
0.70
Varity_R
0.084
gMVP
0.075
Mutation Taster
=100/0
polymorphism

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: rs9972733; hg19: chr16-84203730; API