16-84170123-AGGACGGAGATGGAGAGCCAGAGG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_178452.6(DNAAF1):​c.1300_1322delGGAGATGGAGAGCCAGAGGGGAC​(p.Gly434fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,582,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

DNAAF1
NM_178452.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.03
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-84170123-AGGACGGAGATGGAGAGCCAGAGG-A is Pathogenic according to our data. Variant chr16-84170123-AGGACGGAGATGGAGAGCCAGAGG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 525404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAAF1NM_178452.6 linkc.1300_1322delGGAGATGGAGAGCCAGAGGGGAC p.Gly434fs frameshift_variant 8/12 ENST00000378553.10 NP_848547.4 Q8NEP3-1A0A140VJN4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAAF1ENST00000378553.10 linkc.1300_1322delGGAGATGGAGAGCCAGAGGGGAC p.Gly434fs frameshift_variant 8/121 NM_178452.6 ENSP00000367815.5 Q8NEP3-1
DNAAF1ENST00000563818.5 linkn.977_999delGGAGATGGAGAGCCAGAGGGGAC non_coding_transcript_exon_variant 4/82
DNAAF1ENST00000570298.5 linkn.1454_1476delGGAGATGGAGAGCCAGAGGGGAC non_coding_transcript_exon_variant 8/112
DNAAF1ENST00000563093.5 linkn.1225+75_1226-92delGGAGATGGAGAGCCAGAGGGGAC intron_variant 2 ENSP00000457373.1 Q8NEP3-3

Frequencies

GnomAD3 genomes
AF:
0.0000527
AC:
8
AN:
151692
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251330
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135846
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000186
AC:
266
AN:
1431164
Hom.:
0
AF XY:
0.000166
AC XY:
118
AN XY:
711350
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000189
Gnomad4 NFE exome
AF:
0.000238
Gnomad4 OTH exome
AF:
0.0000854
GnomAD4 genome
AF:
0.0000527
AC:
8
AN:
151692
Hom.:
0
Cov.:
32
AF XY:
0.0000675
AC XY:
5
AN XY:
74094
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000567

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 24, 2021The c.1300_1322del23 pathogenic mutation, located in coding exon 8 of the DNAAF1 gene, results from a deletion of 23 nucleotides at nucleotide positions 1300 to 1322, causing a translational frameshift with a predicted alternate stop codon (p.G434Pfs*4). This alteration was detected along with another DNAAF1 translational frameshift mutation in an individual with primary ciliary dyskinesia (PCD) (Duquesnoy P et al. Am J Hum Genet, 2009 Dec;85:890-6). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 19, 2023This sequence change creates a premature translational stop signal (p.Gly434Profs*4) in the DNAAF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAAF1 are known to be pathogenic (PMID: 19944400, 19944405). This variant is present in population databases (rs745495583, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 19944405). ClinVar contains an entry for this variant (Variation ID: 525404). For these reasons, this variant has been classified as Pathogenic. -
Primary ciliary dyskinesia 13 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 29, 2023- -
DNAAF1-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 12, 2024The DNAAF1 c.1300_1322del23 variant is predicted to result in a frameshift and premature protein termination (p.Gly434Profs*4). This variant has been reported with a second DNAAF1 variant in an individual with primary ciliary dyskinesia (Duquesnoy et al. 2009. PubMed ID: 19944405) and in the heterozygous state in an individual with testicular cancer (Litchfield et al. 2016. PubMed ID: 27996046). At PreventionGenetics, this variant has been detected in the homozygous state in individuals who received testing for ciliopathies (Internal Data). This variant is reported in 0.0062% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in DNAAF1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs745495583; hg19: chr16-84203729; API