rs1555328047

Positions:

• chr14-49634447-CGGGGGCT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018139.3(DNAAF2):​c.696_702delAGCCCCC​(p.Ala233fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,403,650 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DNAAF2 NM_018139.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.48

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 14-49634447-CGGGGGCT-C is Pathogenic according to our data. Variant chr14-49634447-CGGGGGCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 454905.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF2	NM_018139.3	c.696_702delAGCCCCC	p.Ala233fs	frameshift_variant	1/3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2	c.696_702delAGCCCCC	p.Ala233fs	frameshift_variant	1/2		NP_001077377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13	c.696_702delAGCCCCC	p.Ala233fs	frameshift_variant	1/3	1	NM_018139.3	ENSP00000298292.8
DNAAF2	ENST00000406043.3	c.696_702delAGCCCCC	p.Ala233fs	frameshift_variant	1/2	1		ENSP00000384862.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403650 Hom.: 0 AF XY: 0.00000144 AC XY: 1 AN XY: 693790

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: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 09, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DNAAF2 are known to be pathogenic (PMID: 19052621). This variant has not been reported in the literature in individuals with DNAAF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 454905). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Ala233Glyfs*50) in the DNAAF2 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555328047; hg19: chr14-50101165;