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GeneBe

14-73654864-CAA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_031427.4(DNAL1):c.23_24del(p.Lys8ArgfsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 150,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Consequence

DNAL1
NM_031427.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.31
Variant links:
Genes affected
DNAL1 (HGNC:23247): (dynein axonemal light chain 1) This gene encodes an axonemal dynein light chain which functions as a component of the outer dynein arms complex. This complex acts as the molecular motor that provides the force to move cilia in an ATP-dependent manner. The encoded protein is expressed in tissues with motile cilia or flagella and may be involved in the movement of sperm flagella. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jan 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
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. Fraction of 0.962 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-73654864-CAA-C is Pathogenic according to our data. Variant chr14-73654864-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 2671843.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNAL1NM_031427.4 linkuse as main transcriptc.23_24del p.Lys8ArgfsTer16 frameshift_variant 2/8 ENST00000553645.7
DNAL1NM_001201366.2 linkuse as main transcriptc.-95_-94del 5_prime_UTR_variant 3/9
DNAL1XM_017021679.3 linkuse as main transcriptc.-95_-94del 5_prime_UTR_variant 3/9
DNAL1XM_024449715.2 linkuse as main transcriptc.-95_-94del 5_prime_UTR_variant 3/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNAL1ENST00000553645.7 linkuse as main transcriptc.23_24del p.Lys8ArgfsTer16 frameshift_variant 2/81 NM_031427.4 P1Q4LDG9-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000200
AC:
3
AN:
150206
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000737
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
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000200
AC:
3
AN:
150314
Hom.:
0
Cov.:
31
AF XY:
0.0000137
AC XY:
1
AN XY:
73252
show subpopulations
Gnomad4 AFR
AF:
0.0000735
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
Bravo
AF:
0.0000151

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute Of Molecular Biology And Genetics, Federal Almazov National Medical Research CentreDec 11, 2023The c.23_24del variant is 2-bp deletion that creates a premature stop signal (p.Lys8Argfs*16) in the DNAL1 gene and is expected to result in an absent or disrupted protein product. It has a low allele frequency in gnomAD Genomes (Version 3.1.2: f= 0.00002), and, to our knowledge, has not been previously described in PCD-patients either in ClinVar, or in the literature. The proband and her sibling with PCD-phenotype both harbored the c.23_24del in a homozygous state, while the clinically healthy parents were heterozygous carriers of the variant. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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.

Other links and lift over

dbSNP: rs746219926; hg19: chr14-74121567; API