rs760123202

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1PM2PP5_Very_StrongBS1_Supporting

The NM_012472.6(DNAAF11):c.630delG(p.Trp210CysfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000987 in 1,611,532 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

DNAAF11
NM_012472.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 1.74

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 17 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-132632762-AC-A is Pathogenic according to our data. Variant chr8-132632762-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 208996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132632762-AC-A is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000108 (158/1459324) while in subpopulation SAS AF= 0.00161 (139/86210). AF 95% confidence interval is 0.00139. There are 0 homozygotes in gnomad4_exome. There are 120 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF11	NM_012472.6 link	c.630delG	p.Trp210CysfsTer12	frameshift_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.630delG	p.Trp210CysfsTer12	frameshift_variant	Exon 5 of 12	1	NM_012472.6	ENSP00000484634.1		Q86X45-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

251336

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

158

AN:

1459324

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

726184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00161

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 19

Pathogenic:2

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp210Cysfs*12) in the LRRC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LRRC6 are known to be pathogenic (PMID: 23122589). This variant is present in population databases (rs760123202, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 23891469, 24307375). ClinVar contains an entry for this variant (Variation ID: 208996). For these reasons, this variant has been classified as Pathogenic. -

Aug 08, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

DNAAF11-related disorder

Pathogenic:1

Aug 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DNAAF11 c.630delG variant is predicted to result in a frameshift and premature protein termination (p.Trp210Cysfs*12). This particular variant has been reported in the homozygous state in multiple unrelated individuals with primary ciliary dyskinesia with or without situs inversus (Zariwala et al. 2013. PubMed ID: 23891469; Watson et al. 2014. PubMed ID: 24307375, Table S8; Marshall et al. 2015. PubMed ID: 26139845). This variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD and has been classified as pathogenic in ClinVar. Frameshift variants in DNAAF11 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Primary ciliary dyskinesia

Pathogenic:1

Sep 19, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.630delG pathogenic mutation, located in coding exon 5 of the LRRC6 gene, results from a deletion of one nucleotide at nucleotide position 630, causing a translational frameshift with a predicted alternate stop codon (p.W210Cfs*12). This mutation was identified in the homozygous state in affected individuals from 7 primary ciliary dyskinesia families (Zariwala MA et al. Am. J. Hum. Genet., 2013 Aug;93:336-45; Marshall CR et al. G3 (Bethesda), 2015 Jul;5:1775-81). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Kartagener syndrome

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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