rs1060502834

Variant names:

• chr7-729708-A-G
• rs1060502834
• NM_017802.4:c.641A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017802.4(DNAAF5):​c.641A>G​(p.Gln214Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q214H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22
• Publications: 0 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: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26184365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF5	NM_017802.4	c.641A>G	p.Gln214Arg	missense_variant	Exon 2 of 13	ENST00000297440.11	NP_060272.3
DNAAF5	XM_024446813.2	c.641A>G	p.Gln214Arg	missense_variant	Exon 2 of 12		XP_024302581.1
DNAAF5	NR_075098.2	n.618-17A>G		intron_variant	Intron 1 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF5	ENST00000297440.11	c.641A>G	p.Gln214Arg	missense_variant	Exon 2 of 13	1	NM_017802.4	ENSP00000297440.6
DNAAF5	ENST00000438961.1	n.110A>G		non_coding_transcript_exon_variant	Exon 2 of 5	4
DNAAF5	ENST00000440747.5	c.61-17A>G		intron_variant	Intron 1 of 12	2		ENSP00000403165.1
DNAAF5	ENST00000437419.5	c.96+2393A>G		intron_variant	Intron 1 of 4	5		ENSP00000410788.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

May 20, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine with arginine at codon 214 of the DNAAF5 protein (p.Gln214Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DNAAF5-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.0036
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.096
Sift	Benign	0.35	T
Sift4G	Uncertain	0.034	D
Polyphen		0.18	B
Vest4		0.56
MutPred		0.46		Gain of MoRF binding (P = 0.0148);
MVP		0.055
MPC		0.20
ClinPred		0.66	D
GERP RS		5.1
Varity_R		0.13
gMVP		0.25
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1060502834; hg19: chr7-769345;