rs878855036

chr7-780063-CAG-C

Variant summary

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

The NM_017802.4(DNAAF5):c.2353_2354del(p.Ser785GlnfsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,864 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: 6.8e-7 (0 hom.)
• Consequence: DNAAF5 NM_017802.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.74

Genes affected

DNAAF5 (HGNC:26013): (dynein axonemal assembly factor 5) The protein encoded by this gene is essential for the preassembly or stability of axonemal dynein arms, and is found only in organisms with motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia-18, a disorder characterized by abnormalities of motile cilia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

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 7-780063-CAG-C is Pathogenic according to our data. Variant chr7-780063-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 241202.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.2353_2354del	p.Ser785GlnfsTer14	frameshift_variant	12/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.2239+4904_2239+4905del		intron_variant
DNAAF5	NR_075098.2	n.2313_2314del		non_coding_transcript_exon_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.2353_2354del	p.Ser785GlnfsTer14	frameshift_variant	12/13	1	NM_017802.4	P1
DNAAF5	ENST00000403952.3	c.628_629del	p.Ser210GlnfsTer14	frameshift_variant	5/6	1
DNAAF5	ENST00000440747.5	c.1757_1758del	p.Ser587GlnfsTer14	frameshift_variant	12/13	2
DNAAF5	ENST00000461576.1	n.163_164del		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

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

Invitae

Feb 29, 2016

This sequence change deletes 2 nucleotides from exon 12 of the DNAAF5 mRNA (c.2353_2354delAG), causing a frameshift at codon 785. This creates a premature translational stop signal (p.Ser785Glnfs*14) and is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in DNAAF5 are known to be pathogenic (PMID: 24307375, 25232951). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878855036; hg19: chr7-819700;