15-55430733-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_130810.4(DNAAF4):​c.1200A>T​(p.Lys400Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

DNAAF4
NM_130810.4 missense

Scores

3
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.390
Variant links:
Genes affected
DNAAF4 (HGNC:21493): (dynein axonemal assembly factor 4) This gene encodes a tetratricopeptide repeat domain-containing protein. The encoded protein interacts with estrogen receptors and the heat shock proteins, Hsp70 and Hsp90. An homologous protein in rat has been shown to function in neuronal migration in the developing neocortex. A chromosomal translocation involving this gene is associated with a susceptibility to developmental dyslexia. Mutations in this gene are associated with deficits in reading and spelling. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream cell cycle progression 1 (CCPG1) gene. [provided by RefSeq, Mar 2011]
DNAAF4-CCPG1 (HGNC:43019): (DNAAF4-CCPG1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring dyslexia susceptibility 1 candidate 1 (DYX1C1) and cell cycle progression 1 (CCPG1) genes on chromosome 15. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.021340102).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAAF4NM_130810.4 linkc.1200A>T p.Lys400Asn missense_variant Exon 10 of 10 ENST00000321149.7 NP_570722.2 Q8WXU2-1
DNAAF4NM_001033559.3 linkc.1094A>T p.Lys365Ile missense_variant Exon 9 of 9 NP_001028731.1 Q8WXU2-3
DNAAF4NM_001033560.2 linkc.1047+4172A>T intron_variant Intron 8 of 8 NP_001028732.1 Q8WXU2-2A0A0S2Z5Z4
DNAAF4-CCPG1NR_037923.1 linkn.1408+1764A>T intron_variant Intron 8 of 15

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAAF4ENST00000321149.7 linkc.1200A>T p.Lys400Asn missense_variant Exon 10 of 10 1 NM_130810.4 ENSP00000323275.3 Q8WXU2-1

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000531
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000557
AC:
14
AN:
251316
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135846
show subpopulations
Gnomad AFR exome
AF:
0.000677
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000198
AC:
29
AN:
1461200
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
14
AN XY:
726934
show subpopulations
Gnomad4 AFR exome
AF:
0.000717
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000553
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000854
Hom.:
0
Bravo
AF:
0.000117
ExAC
AF:
0.0000741
AC:
9

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2025This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 400 of the DNAAF4 protein (p.Lys400Asn). This variant is present in population databases (rs143213850, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with DNAAF4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1018752). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DNAAF4 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
17
DANN
Uncertain
0.99
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.49
N
LIST_S2
Benign
0.39
T
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.021
T
MetaSVM
Benign
-0.95
T
PROVEAN
Benign
-0.57
N
REVEL
Benign
0.16
Sift
Uncertain
0.012
D
Sift4G
Uncertain
0.045
D
Polyphen
0.96
D
Vest4
0.44
MVP
0.36
ClinPred
0.070
T
GERP RS
4.5

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: rs143213850; hg19: chr15-55722931; API