chr16-84172347-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_178452.6(DNAAF1):c.1616T>C(p.Leu539Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00078 in 1,614,210 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L539M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0040 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00044 ( 6 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.252

Publications

3 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=0.003911704).

BP6

Variant 16-84172347-T-C is Benign according to our data. Variant chr16-84172347-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00404 (616/152366) while in subpopulation AFR AF = 0.0141 (585/41580). AF 95% confidence interval is 0.0131. There are 4 homozygotes in GnomAd4. There are 297 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

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.1616T>C	p.Leu539Pro	missense	Exon 9 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.908T>C	p.Leu303Pro	missense	Exon 5 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.1616T>C	p.Leu539Pro	missense	Exon 9 of 12	ENSP00000367815.5	Q8NEP3-1
DNAAF1	ENST00000963697.1		c.1616T>C	p.Leu539Pro	missense	Exon 9 of 13	ENSP00000633756.1
DNAAF1	ENST00000963694.1		c.1616T>C	p.Leu539Pro	missense	Exon 9 of 13	ENSP00000633753.1

Frequencies

GnomAD3 genomes

AF:

0.00403

AC:

613

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00102

AC:

257

AN:

251448

AF XY:

0.000839

show subpopulations

Gnomad AFR exome

AF:

0.0143

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000440

AC:

643

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

281

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0151

AC:

507

AN:

33480

American (AMR)

AF:

0.000648

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1111976

Other (OTH)

AF:

0.00126

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00404

AC:

616

AN:

152366

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

297

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.0141

AC:

585

AN:

41580

American (AMR)

AF:

0.00150

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68036

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00163

Hom.:

Bravo

AF:

0.00441

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00133

AC:

161

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Primary ciliary dyskinesia (2)

Primary ciliary dyskinesia 13 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.6

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.027

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.94

PhyloP100

-0.25

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.019

Sift

Benign

0.064

Sift4G

Uncertain

0.019

Polyphen

0.022

Vest4

0.20

MVP

0.16

MPC

0.17

ClinPred

0.0083

GERP RS

-5.5

Varity_R

0.14

gMVP

0.38

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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