DNAAF5 p.Leu795Pro

Variant names:

• chr7-780097-T-C
• rs397514561
• NM_017802.4:c.2384T>C
• DNAAF5 p.Leu795Pro

Your query was ambiguous. Multiple possible variants found:

• chr7-780097-T-C
• chr7-780097-TG-CT
• chr7-780097-TG-CC
• chr7-780097-TG-CA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_017802.4(DNAAF5):​c.2384T>C​(p.Leu795Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000750238: Experimental studies have shown that this missense change affects DNAAF5 function (PMID:23040496)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L795L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.52
• Publications: 7 publications found

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]

DNAAF5 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 18

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000750238: Experimental studies have shown that this missense change affects DNAAF5 function (PMID: 23040496).; SCV002559492: Airway epithelial cells from an affected individual showed reduced DNAAF5 levels, absent dynein arms, and loss of ciliary beating (Horani et al., 2012)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 7-780097-T-C is Pathogenic according to our data. Variant chr7-780097-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017802.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	NM_017802.4	MANE Select	c.2384T>C	p.Leu795Pro	missense	Exon 12 of 13	NP_060272.3
	DNAAF5	NR_075098.2		n.2344T>C		non_coding_transcript_exon	Exon 12 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	ENST00000297440.11	TSL:1 MANE Select	c.2384T>C	p.Leu795Pro	missense	Exon 12 of 13	ENSP00000297440.6	Q86Y56-1
	DNAAF5	ENST00000403952.3	TSL:1	c.659T>C	p.Leu220Pro	missense	Exon 5 of 6	ENSP00000384884.3	E9PGY2
	DNAAF5	ENST00000852634.1		c.2465T>C	p.Leu822Pro	missense	Exon 13 of 14	ENSP00000522693.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Primary ciliary dyskinesia (1)
1	-	-	Primary ciliary dyskinesia 18 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.090	T
PhyloP100		5.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.85
Mutation Taster		=5/95	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397514561;

hg19: chr7-819734;