NM_012472.6:c.436G>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3PP3_ModeratePP5_Very_Strong

The NM_012472.6(DNAAF11):c.436G>C(p.Asp146His) variant causes a missense change. The variant allele was found at a frequency of 0.000149 in 1,608,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000772163: Experimental studies have shown that this missense change affects LRRC6 function (PMID:23527195).".

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

DNAAF11
NM_012472.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 6.47

Publications

13 publications found

Variant links:

Genes affected

DNAAF11 (HGNC:16725): (dynein axonemal assembly factor 11) The protein encoded by this gene contains several leucine-rich repeat domains and appears to be involved in the motility of cilia. Defects in this gene are a cause of primary ciliary dyskinesia-19 (CILD19). Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 4, 11 and 22. [provided by RefSeq, Apr 2016]

DNAAF11 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 19
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

DNAAF11 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_012472.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000772163: Experimental studies have shown that this missense change affects LRRC6 function (PMID: 23527195).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

PP5

Variant 8-132632957-C-G is Pathogenic according to our data. Variant chr8-132632957-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012472.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF11	NM_012472.6	MANE Select	c.436G>C	p.Asp146His	missense	Exon 5 of 12	NP_036604.2
DNAAF11	NM_001321961.2		c.436G>C	p.Asp146His	missense	Exon 5 of 11	NP_001308890.1
DNAAF11	NM_001321962.2		c.190G>C	p.Asp64His	missense	Exon 3 of 10	NP_001308891.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAAF11	ENST00000620350.5	TSL:1 MANE Select	c.436G>C	p.Asp146His	missense	Exon 5 of 12	ENSP00000484634.1	Q86X45-1
DNAAF11	ENST00000519595.5	TSL:1	c.436G>C	p.Asp146His	missense	Exon 5 of 12	ENSP00000429791.1	Q86X45-1
DNAAF11	ENST00000250173.5	TSL:1	c.436G>C	p.Asp146His	missense	Exon 5 of 13	ENSP00000250173.2	G5EA20

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000156

AC:

AN:

250332

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000469

Gnomad NFE exome

AF:

0.000300

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000155

AC:

225

AN:

1456056

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

112

AN XY:

724692

show subpopulations

African (AFR)

AF:

0.0000900

AC:

AN:

33320

American (AMR)

AF:

0.0000224

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

86042

European-Finnish (FIN)

AF:

0.0000757

AC:

AN:

52866

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000184

AC:

204

AN:

1107512

Other (OTH)

AF:

0.000199

AC:

AN:

60190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000987

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41374

American (AMR)

AF:

0.00

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

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:

0.000179

Hom.:

Bravo

AF:

0.000117

EpiCase

AF:

0.000218

EpiControl

AF:

0.000297

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia 19 (7)

not provided (2)

Primary ciliary dyskinesia (2)

Heterotaxy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.25

MutationAssessor

Pathogenic

4.0

PhyloP100

6.5

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.7

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Varity_R

0.98

gMVP

0.83

Mutation Taster

=2/98

disease causing (ClinVar)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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