rs727504815

Positions:

• chr14-49634423-C-A
• chr14-49634423-C-T

Variant summary

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

The NM_018139.3(DNAAF2):​c.727G>T​(p.Glu243Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAAF2 NM_018139.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.124

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 14-49634423-C-A is Pathogenic according to our data. Variant chr14-49634423-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179361.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.727G>T	p.Glu243Ter	stop_gained	1/3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2	c.727G>T	p.Glu243Ter	stop_gained	1/2		NP_001077377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13	c.727G>T	p.Glu243Ter	stop_gained	1/3	1	NM_018139.3	ENSP00000298292	P2
DNAAF2	ENST00000406043.3	c.727G>T	p.Glu243Ter	stop_gained	1/2	1		ENSP00000384862	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1416712 Hom.: 0 Cov.: 88 AF XY: 0.00 AC XY: 0 AN XY: 700822

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: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 14, 2014

The Glu243X variant in DNAAF2 has now been reported in the homozygous state in o ne individual with clinical features of primary ciliary dyskinesia (LMM unpublis hed data). In addition, this variant is absent from large population studies. Th is nonsense variant leads to a premature termination codon at position 243, whic h is predicted to lead to a truncated or absent protein. Absence of the DNAAF2 p rotein leads to a loss of ciliary motility and homozygous truncating variants in DNAAF2 (KTU) have been previously reported in two probands and one affected sib ling with primary ciliary dyskinesia (PCD) and left-right body asymmetry (Omran 2008). In summary, the Glu243X variant is likely to be pathogenic, but additiona l studies are needed to fully assess its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Benign	0.035
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.12	N
MutationTaster	Benign	1.0	A;A
Vest4		0.11
GERP RS		-0.20

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

Other links and lift over

dbSNP: rs727504815; hg19: chr14-50101141;