rs200321595

Positions:

chr8-132632957-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_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 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 criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 6.47

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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]. 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/exons	MANE	UniProt
DNAAF11	NM_012472.6 linkuse as main transcript	c.436G>C	p.Asp146His	missense_variant	5/12	ENST00000620350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF11	ENST00000620350.5 linkuse as main transcript	c.436G>C	p.Asp146His	missense_variant	5/12	1	NM_012472.6	P1	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

GnomAD3 exomes

AF:

0.000156

AC:

AN:

250332

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135354

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000900

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000757

Gnomad4 NFE exome

AF:

0.000184

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000987

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

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

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 19

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Aug 20, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2023	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2012	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	-	- -

Primary ciliary dyskinesia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	Dec 11, 2023	ACMG: PP5, PP3, PM2, BP1. The variant has multiple records in ClinVar with pathogenic interpretation (Variation ID: 39798) -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 2023	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. -

Heterotaxy

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Pediatric Genetics Clinic, Sheba Medical Center

Apr 24, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

Jul 13, 2022

- -

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

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;.;.

MutationTaster

Benign

1.0

D;D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over