rs397515341

Variant names:

• chr14-49633935-A-AGCCACGCAGGTATCGT
• rs397515341
• NM_018139.3:c.1199_1214dupACGATACCTGCGTGGC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_018139.3(DNAAF2):​c.1199_1214dupACGATACCTGCGTGGC​(p.Gly406ArgfsTer90) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000719 in 1,530,750 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A405A) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: DNAAF2 NM_018139.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -0.116
• Publications: 5 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 14-49633935-A-AGCCACGCAGGTATCGT is Pathogenic according to our data. Variant chr14-49633935-A-AGCCACGCAGGTATCGT is described in ClinVar as Pathogenic. ClinVar VariationId is 208847.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018139.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	NM_018139.3	MANE Select	c.1199_1214dupACGATACCTGCGTGGC	p.Gly406ArgfsTer90	frameshift	Exon 1 of 3	NP_060609.2	Q9NVR5-1
	DNAAF2	NM_001083908.2		c.1199_1214dupACGATACCTGCGTGGC	p.Gly406ArgfsTer90	frameshift	Exon 1 of 2	NP_001077377.1	Q9NVR5-2
	DNAAF2	NM_001378453.1		c.-673_-658dupACGATACCTGCGTGGC		5_prime_UTR	Exon 1 of 2	NP_001365382.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	ENST00000298292.13	TSL:1 MANE Select	c.1199_1214dupACGATACCTGCGTGGC	p.Gly406ArgfsTer90	frameshift	Exon 1 of 3	ENSP00000298292.8	Q9NVR5-1
	DNAAF2	ENST00000406043.3	TSL:1	c.1199_1214dupACGATACCTGCGTGGC	p.Gly406ArgfsTer90	frameshift	Exon 1 of 2	ENSP00000384862.3	Q9NVR5-2

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151556 Hom.: 0 Cov.: 33

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: 0.000379

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000780 AC: 1 AN: 128198 AF XY: 0.00

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 FIN exome AF: 0.000181

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000508 AC: 7 AN: 1379194 Hom.: 0 Cov.: 91 AF XY: 0.00000441 AC XY: 3 AN XY: 680176

African (AFR) AF: 0.00 AC: 0 AN: 31404

American (AMR) AF: 0.00 AC: 0 AN: 35360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25012

East Asian (EAS) AF: 0.00 AC: 0 AN: 35616

South Asian (SAS) AF: 0.00 AC: 0 AN: 78946

European-Finnish (FIN) AF: 0.000119 AC: 4 AN: 33656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4564

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077060

Other (OTH) AF: 0.0000174 AC: 1 AN: 57576

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151556 Hom.: 0 Cov.: 33 AF XY: 0.0000405 AC XY: 3 AN XY: 74030

African (AFR) AF: 0.00 AC: 0 AN: 41228

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.000379 AC: 4 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67852

Other (OTH) AF: 0.00 AC: 0 AN: 2084

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Primary ciliary dyskinesia 10 (1)
-	-	-	Kartagener syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.12
Mutation Taster		=11/189	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397515341; hg19: chr14-50100653;