rs761527467

Variant names:

• chr14-49634734-T-C
• rs761527467
• NM_018139.3:c.416A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018139.3(DNAAF2):​c.416A>G​(p.Tyr139Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000698 in 1,604,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Y139Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.63
• Publications: 1 publications found

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]

DNAAF2 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 10

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12533042).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018139.3. 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
	DNAAF2	NM_018139.3	MANE Select	c.416A>G	p.Tyr139Cys	missense	Exon 1 of 3	NP_060609.2	Q9NVR5-1
	DNAAF2	NM_001083908.2		c.416A>G	p.Tyr139Cys	missense	Exon 1 of 2	NP_001077377.1	Q9NVR5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	ENST00000298292.13	TSL:1 MANE Select	c.416A>G	p.Tyr139Cys	missense	Exon 1 of 3	ENSP00000298292.8	Q9NVR5-1
	DNAAF2	ENST00000406043.3	TSL:1	c.416A>G	p.Tyr139Cys	missense	Exon 1 of 2	ENSP00000384862.3	Q9NVR5-2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152220 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000614 AC: 14 AN: 227994 AF XY: 0.0000634

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000138

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000689 AC: 100 AN: 1452324 Hom.: 0 Cov.: 98 AF XY: 0.0000775 AC XY: 56 AN XY: 722776

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000225 AC: 1 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.0000219 AC: 1 AN: 45606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000864 AC: 96 AN: 1111108

Other (OTH) AF: 0.0000332 AC: 2 AN: 60190

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152220 Hom.: 0 Cov.: 35 AF XY: 0.0000672 AC XY: 5 AN XY: 74380

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

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

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: 0.000176 AC: 12 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000502 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia (1)
-	1	-	Primary ciliary dyskinesia 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.30	N
PhyloP100		1.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.19
Sift	Benign	0.26	T
Sift4G	Benign	0.18	T
Polyphen		0.024	B
Vest4		0.30
MutPred		0.56		Gain of catalytic residue at R138 (P = 0.0016)
MVP		0.41
MPC		1.6
ClinPred		0.16	T
GERP RS		5.3
PromoterAI		-0.058	Neutral
Varity_R		0.14
gMVP		0.72
Mutation Taster		=91/9	polymorphism

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: rs761527467; hg19: chr14-50101452;