rs760123202

Positions:

• chr8-132632762-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_012472.6(DNAAF11):​c.630del​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.74

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF11	NM_012472.6	c.630del	p.Trp210CysfsTer12	frameshift_variant	5/12	ENST00000620350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF11	ENST00000620350.5	c.630del	p.Trp210CysfsTer12	frameshift_variant	5/12	1	NM_012472.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32

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: 44 AN: 251336 Hom.: 0 AF XY: 0.000250 AC XY: 34 AN XY: 135842

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.: 0 Cov.: 30 AF XY: 0.000165 AC XY: 120 AN XY: 726184

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: 1 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

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:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 19 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	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. -

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2017

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

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs760123202; hg19: chr8-133645008;