16-84170333-C-T

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.1505C>T(p.Pro502Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,613,566 control chromosomes in the GnomAD database, including 107,765 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P502P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.31 ( 7769 hom., cov: 32)

Exomes 𝑓: 0.37 ( 99996 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.826

Publications

24 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=8.3488226E-4).

BP6

Variant 16-84170333-C-T is Benign according to our data. Variant chr16-84170333-C-T is described in ClinVar as [Benign]. Clinvar id is 226575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF1	NM_178452.6 link	c.1505C>T	p.Pro502Leu	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.1505C>T	p.Pro502Leu	missense_variant	Exon 8 of 12	1	NM_178452.6	ENSP00000367815.5		Q8NEP3-1

Frequencies

GnomAD3 genomes

AF:

0.307

AC:

46589

AN:

151974

Hom.:

7761

Cov.:

show subpopulations

Gnomad AFR

AF:

0.160

Gnomad AMI

AF:

0.469

Gnomad AMR

AF:

0.366

Gnomad ASJ

AF:

0.364

Gnomad EAS

AF:

0.329

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.339

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.372

Gnomad OTH

AF:

0.318

GnomAD2 exomes

AF:

0.344

AC:

85585

AN:

248686

AF XY:

0.345

show subpopulations

Gnomad AFR exome

AF:

0.152

Gnomad AMR exome

AF:

0.384

Gnomad ASJ exome

AF:

0.357

Gnomad EAS exome

AF:

0.341

Gnomad FIN exome

AF:

0.340

Gnomad NFE exome

AF:

0.374

Gnomad OTH exome

AF:

0.349

GnomAD4 exome

AF:

0.367

AC:

535884

AN:

1461474

Hom.:

99996

Cov.:

AF XY:

0.364

AC XY:

264345

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.151

AC:

5045

AN:

33480

American (AMR)

AF:

0.383

AC:

17125

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

9394

AN:

26136

East Asian (EAS)

AF:

0.331

AC:

13151

AN:

39696

South Asian (SAS)

AF:

0.286

AC:

24635

AN:

86248

European-Finnish (FIN)

AF:

0.339

AC:

18018

AN:

53138

Middle Eastern (MID)

AF:

0.333

AC:

1922

AN:

5768

European-Non Finnish (NFE)

AF:

0.383

AC:

425583

AN:

1111930

Other (OTH)

AF:

0.348

AC:

21011

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

23892

47783

71675

95566

119458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13372

26744

40116

53488

66860

<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:

0.306

AC:

46609

AN:

152092

Hom.:

7769

Cov.:

AF XY:

0.306

AC XY:

22780

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.160

AC:

6628

AN:

41518

American (AMR)

AF:

0.366

AC:

5593

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

1261

AN:

3468

East Asian (EAS)

AF:

0.330

AC:

1704

AN:

5166

South Asian (SAS)

AF:

0.288

AC:

1388

AN:

4820

European-Finnish (FIN)

AF:

0.339

AC:

3593

AN:

10592

Middle Eastern (MID)

AF:

0.286

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.372

AC:

25272

AN:

67956

Other (OTH)

AF:

0.315

AC:

663

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1627

3253

4880

6506

8133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

472

944

1416

1888

2360

<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:

0.358

Hom.:

21849

Bravo

AF:

0.306

TwinsUK

AF:

0.390

AC:

1445

ALSPAC

AF:

0.383

AC:

1477

ESP6500AA

AF:

0.160

AC:

700

ESP6500EA

AF:

0.370

AC:

3176

ExAC

AF:

0.338

AC:

40957

Asia WGS

AF:

0.269

AC:

933

AN:

3478

EpiCase

AF:

0.368

EpiControl

AF:

0.374

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

May 06, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro502Leu in exon 8 of DNAAF1: This variant is not expected to have clinical s ignificance because it has been identified in 37.5% (24168/64438) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs11644164). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:2

Dec 10, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 13

Benign:2

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.056

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.29

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.0022

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.36

MetaRNN

Benign

0.00083

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.81

PhyloP100

-0.83

PrimateAI

Benign

0.31

PROVEAN

Benign

0.14

REVEL

Benign

0.0060

Sift

Benign

0.53

Sift4G

Benign

0.40

Polyphen

0.0030

Vest4

0.049

MPC

0.020

ClinPred

0.00055

GERP RS

-0.20

Varity_R

0.019

gMVP

0.076

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