NM_001256715.2:c.350G>A

Variant names:

• chr19-55162263-C-T
• rs770403610
• NM_001256715.2:c.350G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001256715.2(DNAAF3):​c.350G>A​(p.Trp117*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000016 in 1,250,628 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: DNAAF3 NM_001256715.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.94
• Publications: 2 publications found

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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-55162263-C-T is Pathogenic according to our data. Variant chr19-55162263-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 572342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF3	NM_001256715.2	c.350G>A	p.Trp117*	stop_gained	Exon 5 of 12	ENST00000524407.7	NP_001243644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF3	ENST00000524407.7	c.350G>A	p.Trp117*	stop_gained	Exon 5 of 12	1	NM_001256715.2	ENSP00000432046.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1098392 Hom.: 0 Cov.: 31 AF XY: 0.0000173 AC XY: 9 AN XY: 518756

African (AFR) AF: 0.00 AC: 0 AN: 23034

American (AMR) AF: 0.000113 AC: 1 AN: 8862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14396

East Asian (EAS) AF: 0.00 AC: 0 AN: 26534

South Asian (SAS) AF: 0.00 AC: 0 AN: 19886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4540

European-Non Finnish (NFE) AF: 0.0000163 AC: 15 AN: 921316

Other (OTH) AF: 0.0000227 AC: 1 AN: 44012

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74376

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 2 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Pathogenic:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp185*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with DNAAF3-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 572342). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.80	D
PhyloP100		1.9
Vest4		0.27
GERP RS		3.4
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs770403610; hg19: chr19-55673631;