chr16-84169989-C-G

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.1161C>G(p.Asp387Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0348 in 1,613,912 control chromosomes in the GnomAD database, including 1,829 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D387D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.064 ( 594 hom., cov: 33)

Exomes 𝑓: 0.032 ( 1235 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.10

Publications

11 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=0.0017419457).

BP6

Variant 16-84169989-C-G is Benign according to our data. Variant chr16-84169989-C-G is described in ClinVar as Benign. ClinVar VariationId is 226571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF1	NM_178452.6 link	c.1161C>G	p.Asp387Glu	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.1161C>G	p.Asp387Glu	missense_variant	Exon 8 of 12	1	NM_178452.6	ENSP00000367815.5		Q8NEP3-1

Frequencies

GnomAD3 genomes

AF:

0.0639

AC:

9728

AN:

152192

Hom.:

595

Cov.:

show subpopulations

Gnomad AFR

AF:

0.162

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0378

Gnomad ASJ

AF:

0.0383

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0500

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0273

Gnomad OTH

AF:

0.0531

GnomAD2 exomes

AF:

0.0363

AC:

9121

AN:

251318

AF XY:

0.0357

show subpopulations

Gnomad AFR exome

AF:

0.162

Gnomad AMR exome

AF:

0.0241

Gnomad ASJ exome

AF:

0.0340

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00545

Gnomad NFE exome

AF:

0.0282

Gnomad OTH exome

AF:

0.0431

GnomAD4 exome

AF:

0.0317

AC:

46349

AN:

1461602

Hom.:

1235

Cov.:

AF XY:

0.0321

AC XY:

23324

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.167

AC:

5595

AN:

33472

American (AMR)

AF:

0.0260

AC:

1164

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0359

AC:

939

AN:

26136

East Asian (EAS)

AF:

0.000202

AC:

AN:

39700

South Asian (SAS)

AF:

0.0541

AC:

4662

AN:

86248

European-Finnish (FIN)

AF:

0.00623

AC:

333

AN:

53416

Middle Eastern (MID)

AF:

0.0878

AC:

487

AN:

5546

European-Non Finnish (NFE)

AF:

0.0276

AC:

30693

AN:

1111998

Other (OTH)

AF:

0.0409

AC:

2468

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

3163

6325

9488

12650

15813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1242

2484

3726

4968

6210

<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:

0.0639

AC:

9736

AN:

152310

Hom.:

594

Cov.:

AF XY:

0.0630

AC XY:

4690

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.162

AC:

6736

AN:

41540

American (AMR)

AF:

0.0377

AC:

577

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0383

AC:

133

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0490

AC:

237

AN:

4832

European-Finnish (FIN)

AF:

0.00442

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0273

AC:

1859

AN:

68032

Other (OTH)

AF:

0.0521

AC:

110

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

452

903

1355

1806

2258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<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:

0.0264

Hom.:

Bravo

AF:

0.0710

TwinsUK

AF:

0.0259

AC:

ALSPAC

AF:

0.0254

AC:

ESP6500AA

AF:

0.154

AC:

678

ESP6500EA

AF:

0.0316

AC:

272

ExAC

AF:

0.0392

AC:

4760

Asia WGS

AF:

0.0290

AC:

101

AN:

3478

EpiCase

AF:

0.0344

EpiControl

AF:

0.0331

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asp387Glu in exon 8 of DNAAF1: This variant is not expected to have clinical s ignificance because it has been identified in 16.3% (1690/10388) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs36062234). -

PreventionGenetics, part of Exact Sciences

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 28, 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. -

Primary ciliary dyskinesia 13

Benign:2

Oct 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

not provided

Benign:2

Mar 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31213628) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.0030

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0032

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

-2.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.9

REVEL

Benign

0.088

Sift

Benign

0.070

Sift4G

Benign

0.17

Polyphen

0.95

Vest4

0.071

MutPred

0.13

Gain of glycosylation at K386 (P = 0.2387);

MPC

0.098

ClinPred

0.039

GERP RS

-1.1

Varity_R

0.048

gMVP

0.11

Mutation Taster

=93/7

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