14-49633463-C-T

Position:

• chr14-49633463-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018139.3(DNAAF2):​c.1687G>A​(p.Ala563Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A563S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.459

Genes affected

DNAAF2 (HGNC:20188): (dynein axonemal assembly factor 2) This gene encodes a highly conserved protein involved in the preassembly of dynein arm complexes which power cilia. These complexes are found in some cilia and are assembled in the cytoplasm prior to transport for cilia formation. Mutations in this gene have been associated with primary ciliary dyskinesia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043631613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF2	NM_018139.3	c.1687G>A	p.Ala563Thr	missense_variant	1/3	ENST00000298292.13
DNAAF2	NM_001083908.2	c.1687G>A	p.Ala563Thr	missense_variant	1/2
DNAAF2	NM_001378453.1	c.-205+20G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF2	ENST00000298292.13	c.1687G>A	p.Ala563Thr	missense_variant	1/3	1	NM_018139.3	P2
DNAAF2	ENST00000406043.3	c.1687G>A	p.Ala563Thr	missense_variant	1/2	1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.2
DANN	Benign	0.86
DEOGEN2	Benign	0.00027	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.7	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.021
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.057
MutPred		0.44		Gain of catalytic residue at Y568 (P = 0.039);Gain of catalytic residue at Y568 (P = 0.039);
MVP		0.14
MPC		0.49
ClinPred		0.071	T
GERP RS		1.5
Varity_R		0.040
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138511448; hg19: chr14-50100181;