chr16-84176132-T-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.1898T>C(p.Leu633Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,613,394 control chromosomes in the GnomAD database, including 100,022 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. L633F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.29 ( 7327 hom., cov: 32)

Exomes 𝑓: 0.35 ( 92695 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.12

Publications

45 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=3.13282E-4).

BP6

Variant 16-84176132-T-C is Benign according to our data. Variant chr16-84176132-T-C is described in ClinVar as Benign. ClinVar VariationId is 163087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF1	NM_178452.6 link	c.1898T>C	p.Leu633Ser	missense_variant	Exon 11 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.1898T>C	p.Leu633Ser	missense_variant	Exon 11 of 12	1	NM_178452.6	ENSP00000367815.5		Q8NEP3-1

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43702

AN:

151810

Hom.:

7313

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.444

Gnomad AMR

AF:

0.389

Gnomad ASJ

AF:

0.304

Gnomad EAS

AF:

0.370

Gnomad SAS

AF:

0.272

Gnomad FIN

AF:

0.367

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.354

Gnomad OTH

AF:

0.293

GnomAD2 exomes

AF:

0.345

AC:

86355

AN:

250160

AF XY:

0.343

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.472

Gnomad ASJ exome

AF:

0.294

Gnomad EAS exome

AF:

0.375

Gnomad FIN exome

AF:

0.364

Gnomad NFE exome

AF:

0.358

Gnomad OTH exome

AF:

0.337

GnomAD4 exome

AF:

0.352

AC:

514435

AN:

1461466

Hom.:

92695

Cov.:

AF XY:

0.349

AC XY:

253665

AN XY:

727002

show subpopulations

African (AFR)

AF:

0.0967

AC:

3237

AN:

33474

American (AMR)

AF:

0.464

AC:

20700

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

7765

AN:

26132

East Asian (EAS)

AF:

0.377

AC:

14947

AN:

39692

South Asian (SAS)

AF:

0.269

AC:

23197

AN:

86258

European-Finnish (FIN)

AF:

0.362

AC:

19325

AN:

53370

Middle Eastern (MID)

AF:

0.273

AC:

1574

AN:

5768

European-Non Finnish (NFE)

AF:

0.363

AC:

403784

AN:

1111750

Other (OTH)

AF:

0.330

AC:

19906

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

21467

42934

64402

85869

107336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12858

25716

38574

51432

64290

<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:

0.288

AC:

43724

AN:

151928

Hom.:

7327

Cov.:

AF XY:

0.292

AC XY:

21664

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.108

AC:

4488

AN:

41426

American (AMR)

AF:

0.390

AC:

5951

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

1052

AN:

3466

East Asian (EAS)

AF:

0.371

AC:

1904

AN:

5136

South Asian (SAS)

AF:

0.272

AC:

1309

AN:

4816

European-Finnish (FIN)

AF:

0.367

AC:

3873

AN:

10560

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.354

AC:

24054

AN:

67952

Other (OTH)

AF:

0.290

AC:

611

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1523

3046

4570

6093

7616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

442

884

1326

1768

2210

<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:

0.329

Hom.:

29809

Bravo

AF:

0.287

TwinsUK

AF:

0.376

AC:

1394

ALSPAC

AF:

0.358

AC:

1379

ESP6500AA

AF:

0.111

AC:

489

ESP6500EA

AF:

0.355

AC:

3054

ExAC

AF:

0.336

AC:

40791

Asia WGS

AF:

0.282

AC:

981

AN:

3478

EpiCase

AF:

0.343

EpiControl

AF:

0.348

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu633Ser in exon 11 of DNAAF1: This variant is not expected to have clinical si gnificance because it has been identified in 35.5% (3054/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs2288020). -

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 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. -

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

- -

Primary ciliary dyskinesia 13

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.010

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.0099

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.21

T;T

MetaRNN

Benign

0.00031

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.85

L;.

PhyloP100

-3.1

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.68

N;N

REVEL

Benign

0.030

Sift

Benign

0.74

T;T

Sift4G

Benign

0.83

T;T

Polyphen

0.10

B;.

Vest4

0.034

MPC

0.022

ClinPred

0.0045

GERP RS

-3.4

PromoterAI

0.023

Neutral

(source)

Varity_R

0.023

gMVP

0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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