rs387907151

Positions:

• chr19-55165904-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001256715.2(DNAAF3):​c.182T>C​(p.Leu61Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 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 (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAAF3 NM_001256715.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.13

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 19-55165904-A-G is Pathogenic according to our data. Variant chr19-55165904-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 31532.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF3	NM_001256715.2	c.182T>C	p.Leu61Pro	missense_variant	3/12	ENST00000524407.7
DNAAF3-AS1	XR_007067344.1	n.442A>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF3	ENST00000524407.7	c.182T>C	p.Leu61Pro	missense_variant	3/12	1	NM_001256715.2	A2
DNAAF3-AS1	ENST00000591665.1	n.1186+3103A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

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.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 04, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics, Clalit Research Institute, Clalit Health Care	Sep 05, 2024	Inheritance: The variant was identified in the Homozygous state in the sample. Frequency: The variant is absent from the gnomAD reference population dataset. Allelic data: This variant was previously reported in a homozgote state (PMID:22387996). Frequency among cases: This variant was identified in homozygous state in several PCD individuals from the Bedouin subpopulation. Segregation: The variant is segregate with disease in multiple affected family members in a gene definitively known to cause disease (PMID:22387996). Prediction tools: REVEL predicts an uncertain impact on the gene or gene product (score 0.42). Clinical evidence: This variant has previously been described in ClinVar (VCV31532) with the following classifications: P (1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;.;D;D;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.59	T;T;T;T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.1	.;.;D;.;.;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	.;.;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;.
Polyphen		0.36	B;.;.;.;.;.
Vest4		0.77
MutPred		0.74		Loss of stability (P = 0.0152);.;.;Loss of stability (P = 0.0152);.;.;
MVP		0.61
MPC		1.2
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.71
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs387907151; hg19: chr19-55677272;