rs397515339

chr16-84170172-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_178452.6(DNAAF1):c.1349dup(p.Pro451AlafsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAAF1 NM_178452.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.74

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-84170172-A-AC is Pathogenic according to our data. Variant chr16-84170172-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 263.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.1349dup	p.Pro451AlafsTer6	frameshift_variant	8/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1349dup	p.Pro451AlafsTer6	frameshift_variant	8/12	1	NM_178452.6	P1
DNAAF1	ENST00000563818.5	n.1026dup		non_coding_transcript_exon_variant	4/8	2
DNAAF1	ENST00000570298.5	n.1503dup		non_coding_transcript_exon_variant	8/11	2
DNAAF1	ENST00000563093.5	c.1226-65dup		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1459068 Hom.: 0 Cov.: 95 AF XY: 0.00 AC XY: 0 AN XY: 725750

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change creates a premature translational stop signal (p.Pro451Alafs*6) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 19944400). ClinVar contains an entry for this variant (Variation ID: 263). For these reasons, this variant has been classified as Pathogenic. -

Primary ciliary dyskinesia 13 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2009

- -

Kartagener syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

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: rs397515339; hg19: chr16-84203778;