rs769220870

chr8-132661557-CGA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_012472.6(DNAAF11):c.79_80del(p.Ser27ValfsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,846 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S27S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000089 (1 hom.)
• Consequence: DNAAF11 NM_012472.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.37

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-132661557-CGA-C is Pathogenic according to our data. Variant chr8-132661557-CGA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540327.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF11	NM_012472.6	c.79_80del	p.Ser27ValfsTer13	frameshift_variant	2/12	ENST00000620350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF11	ENST00000620350.5	c.79_80del	p.Ser27ValfsTer13	frameshift_variant	2/12	1	NM_012472.6	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251288 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000889 AC: 130 AN: 1461662 Hom.: 1 AF XY: 0.0000866 AC XY: 63 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000477 Hom.: 0

Bravo AF: 0.0000945

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 19 Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 25, 2023	This sequence change creates a premature translational stop signal (p.Ser27Valfs*13) 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 (rs769220870, gnomAD 0.4%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 33447612). ClinVar contains an entry for this variant (Variation ID: 540327). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The LRRC6 c.79_80delTC (p.Ser27ValfsTer13) variant results in a frameshift and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. Based on this search no publications were found reporting the p.Ser27ValfsTer13 variant in association with primary ciliary dyskinesia, however the p.Ser27ValfsTer13 variant was reported in one study, segregating in an autosomal dominant manner across a father and son with testicular germ cell tumor (Litchfield et al. 2016). The p.Ser27ValfsTer13 was absent from 1644 UK population control subjects but is reported at a frequency of 0.004140 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the limited evidence, the frequency databases and the potential impact on protein expression, the LRRC6 is classified as a variant of unknown significance but suspicious for pathogenicity for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Columbia University Laboratory of Personalized Genomic Medicine, Columbia University Medical Center	Feb 05, 2021	Whole exome sequencing of the proband and parents identified heterozygous p.S27Vfs*13 variants in both the mother and father and the homozygous variant in the proband. The proband was found to have situs inversus and polysplenia at birth. The variant is present in the population at low level (gnomAD: 45/251288=0.000179). The p.S27Vfs*13 variant has been reported once as a homozygous variant in a patient with primary ciliary dyskinesia (Gileles-Hillel, 2020 (PMID: 33447612)). The proband is the product of a nonconsanguineous union between two parents of Ashkenazi Jewish descent with family histories negative for similarly affected individuals. While no functional data for this variant is available, in vitro studies of downstream truncating variants are recognized loss-of-function causes of autosomal recessive primary ciliary dyskinesia-19 (Kott 2012 (PMID: 23122589), Zariwala 2013 (PubMed: 23891469)). -

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: PVS1, PM2, PM3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 20, 2020	The c.79_80delTC pathogenic mutation, located in coding exon 2 of the LRRC6 gene, results from a deletion of two nucleotides at nucleotide positions 79 to 80, causing a translational frameshift with a predicted alternate stop codon (p.S27Vfs*13). 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. -

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: rs769220870; hg19: chr8-133673803;