19-55160690-TC-TCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001256715.2(DNAAF3):c.997_998insG(p.Asp333GlyfsTer64) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,613,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D333D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: DNAAF3 NM_001256715.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.16

Genes affected

DNAAF3 (HGNC:30492): (dynein axonemal assembly factor 3) The protein encoded by this gene is required for the assembly of axonemal inner and outer dynein arms and plays a role in assembling dynein complexes for transport into cilia. Defects in this gene are a cause of primary ciliary dyskinesia type 2 (CILD2). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

DNAAF3-AS1 (HGNC:55292): (DNAAF3 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 18 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 19-55160690-T-TC is Pathogenic according to our data. Variant chr19-55160690-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 410279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF3	NM_001256715.2	c.997_998insG	p.Asp333GlyfsTer64	frameshift_variant	9/12	ENST00000524407.7
DNAAF3-AS1	XR_007067344.1	n.138-349dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF3	ENST00000524407.7	c.997_998insG	p.Asp333GlyfsTer64	frameshift_variant	9/12	1	NM_001256715.2	A2
DNAAF3-AS1	ENST00000591665.1	n.968-349dup		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151840 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000968

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000768 AC: 19 AN: 247378 Hom.: 0 AF XY: 0.0000669 AC XY: 9 AN XY: 134504

Gnomad AFR exome AF: 0.0000653

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000949

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000181 AC: 265 AN: 1461334 Hom.: 0 Cov.: 33 AF XY: 0.000176 AC XY: 128 AN XY: 727004

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.000226

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000105 AC: 16 AN: 151958 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74282

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000110

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with DNAAF3 related disorder (ClinVar ID: VCV000410279 / PMID: 31213628). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2023

This sequence change creates a premature translational stop signal (p.Asp401Glyfs*63) in the DNAAF3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAAF3 are known to be pathogenic (PMID: 22387996). This variant is present in population databases (rs756430359, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DNAAF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 410279). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs756430359; hg19: chr19-55672058;