8-132675492-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_012472.6(DNAAF11):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000701 in 1,568,516 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

DNAAF11
NM_012472.6 start_lost

Scores

5
8
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 3.35
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-132675492-A-T is Pathogenic according to our data. Variant chr8-132675492-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540324.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAAF11NM_012472.6 linkc.2T>A p.Met1? start_lost 1/12 ENST00000620350.5 NP_036604.2 Q86X45-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAAF11ENST00000620350.5 linkc.2T>A p.Met1? start_lost 1/121 NM_012472.6 ENSP00000484634.1 Q86X45-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152160
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000901
AC:
2
AN:
221990
Hom.:
0
AF XY:
0.00000828
AC XY:
1
AN XY:
120744
show subpopulations
Gnomad AFR exome
AF:
0.000147
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000353
AC:
5
AN:
1416356
Hom.:
0
Cov.:
30
AF XY:
0.00000142
AC XY:
1
AN XY:
703728
show subpopulations
Gnomad4 AFR exome
AF:
0.0000963
Gnomad4 AMR exome
AF:
0.0000248
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152160
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.000145
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 19 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 11, 2023This sequence change affects the initiator methionine of the LRRC6 mRNA. The next in-frame methionine is located at codon 121. This variant is present in population databases (rs377278570, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with LRRC6-related conditions. ClinVar contains an entry for this variant (Variation ID: 540324). This variant disrupts a region of the LRRC6 protein in which other variant(s) (p.Ile100Thr) have been determined to be pathogenic (PMID: 27637300). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Primary ciliary dyskinesia Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 08, 2023The p.M1? pathogenic mutation (also known as c.2T>A) is located in coding exon 1 of the LRRC6 gene and results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. However, there is an alternative initiation (or start) codon in other clinically/biologically relevant transcript(s). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 30, 2023The DNAAF11 c.2T>A; p.Met1? variant (rs377278570), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 540324). This variant is found in the African/African-American population with an allele frequency of 0.027% (6/22,344 alleles) in the Genome Aggregation Database. Additionally, a downstream truncating variant has been described in an individual with primary ciliary dyskinesia and is considered pathogenic (Tinoco 2023). The p.Met1 variant abolishes the canonical translation initiation site, which is likely to disrupt gene function. Based on available information, this variant is considered to be likely pathogenic. References: Tinoco EM et al. Primary Ciliary Dyskinesia in a Portuguese Bronchiectasis Outpatient Clinic. Genes (Basel). 2023 Feb 21;14(3):541. PMID: 36980814. -
DNAAF11-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 01, 2023The DNAAF11 c.2T>A variant is predicted to disrupt the translation initiation site (Start loss). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.027% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-133687738-A-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.17
T;T;T;T
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.90
D;.;.;D
M_CAP
Pathogenic
0.75
D
MetaRNN
Pathogenic
0.84
D;D;D;D
MetaSVM
Benign
-0.57
T
PROVEAN
Uncertain
-3.1
.;D;D;D
REVEL
Uncertain
0.41
Sift
Uncertain
0.0010
.;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
0.99
D;D;.;.
Vest4
0.89
MVP
0.36
ClinPred
0.97
D
GERP RS
3.7
Varity_R
0.92
gMVP
0.78

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.

Other links and lift over

dbSNP: rs377278570; hg19: chr8-133687738; API