chr16-84170124-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_178452.6(DNAAF1):c.1296G>C(p.Glu432Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0876 in 1,605,926 control chromosomes in the GnomAD database, including 7,175 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E432K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.079 ( 514 hom., cov: 32)

Exomes 𝑓: 0.088 ( 6661 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.933

Publications

19 publications found

Variant links:

Genes affected

DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DNAAF1 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 13
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAAF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00406757).

BP6

Variant 16-84170124-G-C is Benign according to our data. Variant chr16-84170124-G-C is described in ClinVar as [Benign]. Clinvar id is 226573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF1	NM_178452.6 link	c.1296G>C	p.Glu432Asp	missense_variant	Exon 8 of 12	ENST00000378553.10	NP_848547.4	Q8NEP3-1A0A140VJN4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF1	ENST00000378553.10 link	c.1296G>C	p.Glu432Asp	missense_variant	Exon 8 of 12	1	NM_178452.6	ENSP00000367815.5		Q8NEP3-1

Frequencies

GnomAD3 genomes

AF:

0.0790

AC:

11995

AN:

151784

Hom.:

512

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0572

Gnomad AMI

AF:

0.131

Gnomad AMR

AF:

0.0587

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.139

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.0707

Gnomad MID

AF:

0.0764

Gnomad NFE

AF:

0.0830

Gnomad OTH

AF:

0.0891

GnomAD2 exomes

AF:

0.0945

AC:

23744

AN:

251252

AF XY:

0.101

show subpopulations

Gnomad AFR exome

AF:

0.0577

Gnomad AMR exome

AF:

0.0439

Gnomad ASJ exome

AF:

0.104

Gnomad EAS exome

AF:

0.123

Gnomad FIN exome

AF:

0.0752

Gnomad NFE exome

AF:

0.0836

Gnomad OTH exome

AF:

0.0923

GnomAD4 exome

AF:

0.0885

AC:

128618

AN:

1454026

Hom.:

6661

Cov.:

100

AF XY:

0.0924

AC XY:

66852

AN XY:

723348

show subpopulations

African (AFR)

AF:

0.0556

AC:

1852

AN:

33296

American (AMR)

AF:

0.0464

AC:

2054

AN:

44266

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

2739

AN:

25782

East Asian (EAS)

AF:

0.152

AC:

5998

AN:

39566

South Asian (SAS)

AF:

0.202

AC:

17431

AN:

86104

European-Finnish (FIN)

AF:

0.0748

AC:

3989

AN:

53308

Middle Eastern (MID)

AF:

0.0824

AC:

460

AN:

5580

European-Non Finnish (NFE)

AF:

0.0798

AC:

88325

AN:

1106180

Other (OTH)

AF:

0.0963

AC:

5770

AN:

59944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

8871

17742

26613

35484

44355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3294

6588

9882

13176

16470

<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:

0.0791

AC:

12014

AN:

151900

Hom.:

514

Cov.:

AF XY:

0.0809

AC XY:

6009

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.0574

AC:

2377

AN:

41428

American (AMR)

AF:

0.0586

AC:

895

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

356

AN:

3466

East Asian (EAS)

AF:

0.138

AC:

712

AN:

5146

South Asian (SAS)

AF:

0.199

AC:

953

AN:

4788

European-Finnish (FIN)

AF:

0.0707

AC:

747

AN:

10560

Middle Eastern (MID)

AF:

0.0753

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0830

AC:

5639

AN:

67928

Other (OTH)

AF:

0.0919

AC:

194

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

534

1067

1601

2134

2668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0701

Hom.:

167

Bravo

AF:

0.0756

TwinsUK

AF:

0.0863

AC:

320

ALSPAC

AF:

0.0786

AC:

303

ESP6500AA

AF:

0.0559

AC:

246

ESP6500EA

AF:

0.0844

AC:

726

ExAC

AF:

0.0971

AC:

11783

Asia WGS

AF:

0.183

AC:

636

AN:

3478

EpiCase

AF:

0.0863

EpiControl

AF:

0.0859

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu432Asp in exon 8 of DNAAF1: This variant is not expected to have clinical s ignificance because it has been identified in 20% (3315/16512) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs9972733). -

Primary ciliary dyskinesia 13

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 11, 2014

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:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.58

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.0057

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0053

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

-0.93

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.63

REVEL

Benign

0.019

Sift

Benign

0.099

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.022

MutPred

0.11

Loss of methylation at K430 (P = 0.0922);

MPC

0.019

ClinPred

0.0057

GERP RS

0.70

Varity_R

0.084

gMVP

0.075

Mutation Taster

=100/0

polymorphism (auto)

(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