14-49633745-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018139.3(DNAAF2):c.1405T>A(p.Cys469Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,593,752 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C469Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 9 hom. )

Consequence

DNAAF2
NM_018139.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.995

Publications

3 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043182373).

BP6

Variant 14-49633745-A-T is Benign according to our data. Variant chr14-49633745-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241280.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0021 (320/152270) while in subpopulation NFE AF = 0.00375 (255/68010). AF 95% confidence interval is 0.00337. There are 0 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DNAAF2	NM_018139.3 link	c.1405T>A	p.Cys469Ser	missense_variant	Exon 1 of 3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2 link	c.1405T>A	p.Cys469Ser	missense_variant	Exon 1 of 2		NP_001077377.1
DNAAF2	NM_001378453.1 link	c.-467T>A		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.1405T>A	p.Cys469Ser	missense_variant	Exon 1 of 3	1	NM_018139.3	ENSP00000298292.8
DNAAF2	ENST00000406043.3 link	c.1405T>A	p.Cys469Ser	missense_variant	Exon 1 of 2	1		ENSP00000384862.3

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

320

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00405

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00375

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00178

AC:

414

AN:

232926

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000215

Gnomad ASJ exome

AF:

0.00365

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00469

Gnomad NFE exome

AF:

0.00269

Gnomad OTH exome

AF:

0.000888

GnomAD4 exome

AF:

0.00163

AC:

2347

AN:

1441482

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

1185

AN XY:

715892

show subpopulations

African (AFR)

AF:

0.0000910

AC:

AN:

32964

American (AMR)

AF:

0.000211

AC:

AN:

42716

Ashkenazi Jewish (ASJ)

AF:

0.00405

AC:

102

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

39510

South Asian (SAS)

AF:

0.00

AC:

AN:

84820

European-Finnish (FIN)

AF:

0.00553

AC:

262

AN:

47394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.00169

AC:

1866

AN:

1103690

Other (OTH)

AF:

0.00176

AC:

105

AN:

59542

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

162

324

487

649

811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00210

AC:

320

AN:

152270

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41560

American (AMR)

AF:

0.000458

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00405

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00375

AC:

255

AN:

68010

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.00272

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00129

AC:

ExAC

AF:

0.00165

AC:

200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 10

Uncertain:1Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Mar 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:2

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNAAF2: BP4, BS2 -

DNAAF2-related disorder

Benign:1

Dec 13, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.024

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.00052

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.27

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;N

PhyloP100

-0.99

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.010

Sift

Benign

0.46

T;T

Sift4G

Benign

0.63

T;T

Polyphen

0.0

B;B

Vest4

0.047

MutPred

0.30

Gain of catalytic residue at G465 (P = 5e-04);Gain of catalytic residue at G465 (P = 5e-04);

MVP

0.095

MPC

0.63

ClinPred

0.012

GERP RS

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.064

gMVP

0.30

Mutation Taster

=98/2

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