NM_012472.6:c.436G>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_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 (★★).

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:9O: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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen

DNAAF11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

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 CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632957-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF11	NM_012472.6 link	c.436G>C	p.Asp146His	missense_variant	Exon 5 of 12	ENST00000620350.5	NP_036604.2	Q86X45-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF11	ENST00000620350.5 link	c.436G>C	p.Asp146His	missense_variant	Exon 5 of 12	1	NM_012472.6	ENSP00000484634.1		Q86X45-1

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

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000297

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 19

Pathogenic:4Other:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 146 of the LRRC6 protein (p.Asp146His). This variant is present in population databases (rs200321595, gnomAD 0.03%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23122589, 23527195, 23891469). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39798). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LRRC6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LRRC6 function (PMID: 23527195). For these reasons, this variant has been classified as Pathogenic. -

Nov 02, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 20, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -

Hadassah Hebrew University Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Primary ciliary dyskinesia

Pathogenic:2

Dec 11, 2023

Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG: PP5, PP3, PM2, BP1. The variant has multiple records in ClinVar with pathogenic interpretation (Variation ID: 39798) -

Sep 01, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D146H pathogenic mutation (also known as c.436G>C), located in coding exon 5 of the LRRC6 gene, results from a G to C substitution at nucleotide position 436. The aspartic acid at codon 146 is replaced by histidine, an amino acid with similar properties. This mutation was identified in the compound heterozygous state in two individuals with primary ciliary dyskinesia (PCD) and absent dynein arms (Kott E et al. Am. J. Hum. Genet., 2012 Nov;91:958-64; Zariwala MA et al. Am. J. Hum. Genet., 2013 Aug;93:336-45). It was also identified in the homozyogus state is 5 individuals with PCD from 2 unrelated families; all five individuals had absent dynein arms and three had situs abnormalities (Horani A et al. PLoS ONE, 2013 Mar;8:e59436). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:2

Aug 22, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31589614, 38193396, 34693619, 23527195, 34215651, 33726816, 31879361, 23891469, 35768906, 31980526, 33635866, 33447612, 37077557, 23122589) -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Heterotaxy

Pathogenic:1

Apr 24, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

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

.;T;T;T;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;.;.;D

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.86

D;D;D;D;D

MetaSVM

Uncertain

0.25

MutationAssessor

Pathogenic

4.0

.;H;H;.;.

PhyloP100

6.5

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.7

.;.;D;D;D

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

.;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;D;D;.;.

Vest4

0.93

MVP

0.57

MPC

0.45

ClinPred

0.97

GERP RS

5.3

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

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