14-49633922-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018139.3(DNAAF2):c.1228T>C(p.Ser410Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,531,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. S410S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

DNAAF2
NM_018139.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -3.81

Publications

0 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAAF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056716233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF2	NM_018139.3 link	c.1228T>C	p.Ser410Pro	missense_variant	Exon 1 of 3	ENST00000298292.13	NP_060609.2	Q9NVR5-1
DNAAF2	NM_001083908.2 link	c.1228T>C	p.Ser410Pro	missense_variant	Exon 1 of 2		NP_001077377.1	Q9NVR5-2
DNAAF2	NM_001378453.1 link	c.-644T>C		5_prime_UTR_variant	Exon 1 of 2		NP_001365382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13 link	c.1228T>C	p.Ser410Pro	missense_variant	Exon 1 of 3	1	NM_018139.3	ENSP00000298292.8		Q9NVR5-1
DNAAF2	ENST00000406043.3 link	c.1228T>C	p.Ser410Pro	missense_variant	Exon 1 of 2	1		ENSP00000384862.3		Q9NVR5-2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151586

Hom.:

Cov.:

show subpopulations

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:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000542

AC:

AN:

129264

AF XY:

0.0000849

show subpopulations

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:

0.000144

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000149

AC:

205

AN:

1379686

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

680382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31426

American (AMR)

AF:

0.0000282

AC:

AN:

35494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25058

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35648

South Asian (SAS)

AF:

0.00

AC:

AN:

79026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4622

European-Non Finnish (NFE)

AF:

0.000184

AC:

198

AN:

1077186

Other (OTH)

AF:

0.0000868

AC:

AN:

57602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151586

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74048

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41232

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67844

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000480

Hom.:

ExAC

AF:

0.0000147

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2

May 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S410P variant (also known as c.1228T>C), located in coding exon 1 of the DNAAF2 gene, results from a T to C substitution at nucleotide position 1228. The serine at codon 410 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Jun 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 410 of the DNAAF2 protein (p.Ser410Pro). This variant is present in population databases (rs746189091, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DNAAF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 454898). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.1

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0053

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0085

LIST_S2

Benign

0.37

T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;L

PhyloP100

-3.8

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.82

N;N

REVEL

Benign

0.010

Sift

Benign

0.18

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0

B;B

Vest4

0.057

MutPred

0.22

Gain of catalytic residue at V412 (P = 0);Gain of catalytic residue at V412 (P = 0);

MVP

0.10

MPC

0.72

ClinPred

0.055

GERP RS

-3.6

Varity_R

0.078

gMVP

0.25

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over