rs2288022

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1976T>C(p.Leu659Pro) 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 1,613,468 control chromosomes in the GnomAD database, including 99,929 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. L659V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.29 ( 7331 hom., cov: 32)

Exomes 𝑓: 0.35 ( 92598 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00900

Publications

29 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: ClinGen, Labcorp Genetics (formerly Invitae)
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=2.1257997E-4).

BP6

Variant 16-84176210-T-C is Benign according to our data. Variant chr16-84176210-T-C is described in ClinVar as Benign. ClinVar VariationId is 163089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178452.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF1	NM_178452.6	MANE Select	c.1976T>C	p.Leu659Pro	missense	Exon 11 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.1268T>C	p.Leu423Pro	missense	Exon 7 of 8	NP_001305685.1	Q8NEP3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAAF1	ENST00000378553.10	TSL:1 MANE Select	c.1976T>C	p.Leu659Pro	missense	Exon 11 of 12	ENSP00000367815.5	Q8NEP3-1
DNAAF1	ENST00000963697.1		c.1982T>C	p.Leu661Pro	missense	Exon 11 of 13	ENSP00000633756.1
DNAAF1	ENST00000963694.1		c.1976T>C	p.Leu659Pro	missense	Exon 11 of 13	ENSP00000633753.1

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43742

AN:

152020

Hom.:

7317

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.444

Gnomad AMR

AF:

0.390

Gnomad ASJ

AF:

0.303

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:

0.294

GnomAD2 exomes

AF:

0.345

AC:

86434

AN:

250758

AF XY:

0.342

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.472

Gnomad ASJ exome

AF:

0.294

Gnomad EAS exome

AF:

0.375

Gnomad FIN exome

AF:

0.363

Gnomad NFE exome

AF:

0.357

Gnomad OTH exome

AF:

0.337

GnomAD4 exome

AF:

0.352

AC:

514114

AN:

1461330

Hom.:

92598

Cov.:

AF XY:

0.349

AC XY:

253537

AN XY:

726966

show subpopulations

African (AFR)

AF:

0.0966

AC:

3234

AN:

33480

American (AMR)

AF:

0.463

AC:

20707

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

7766

AN:

26136

East Asian (EAS)

AF:

0.377

AC:

14953

AN:

39692

South Asian (SAS)

AF:

0.269

AC:

23208

AN:

86250

European-Finnish (FIN)

AF:

0.362

AC:

19192

AN:

53004

Middle Eastern (MID)

AF:

0.273

AC:

1574

AN:

5768

European-Non Finnish (NFE)

AF:

0.363

AC:

403582

AN:

1111930

Other (OTH)

AF:

0.330

AC:

19898

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

20952

41904

62855

83807

104759

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12854

25708

38562

51416

64270

<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:

43764

AN:

152138

Hom.:

7331

Cov.:

AF XY:

0.292

AC XY:

21697

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.108

AC:

4489

AN:

41546

American (AMR)

AF:

0.391

AC:

5985

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

1050

AN:

3468

East Asian (EAS)

AF:

0.370

AC:

1908

AN:

5152

South Asian (SAS)

AF:

0.272

AC:

1314

AN:

4830

European-Finnish (FIN)

AF:

0.367

AC:

3881

AN:

10580

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.354

AC:

24042

AN:

67954

Other (OTH)

AF:

0.291

AC:

613

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1546

3091

4637

6182

7728

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.336

Hom.:

15111

Bravo

AF:

0.287

TwinsUK

AF:

0.375

AC:

1391

ALSPAC

AF:

0.358

AC:

1378

ESP6500AA

AF:

0.109

AC:

480

ESP6500EA

AF:

0.351

AC:

3017

ExAC

AF:

0.336

AC:

40766

Asia WGS

AF:

0.282

AC:

981

AN:

3478

EpiCase

AF:

0.343

EpiControl

AF:

0.347

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Primary ciliary dyskinesia (2)

Primary ciliary dyskinesia 13 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.81

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.0013

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.17

MetaRNN

Benign

0.00021

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.34

PhyloP100

0.0090

PrimateAI

Benign

0.25

PROVEAN

Benign

2.1

REVEL

Benign

0.077

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.019

MPC

0.023

ClinPred

0.0032

GERP RS

2.3

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.042

gMVP

0.062

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over