14-73654864-CAA-C

Variant names:

• chr14-73654864-CAA-C
• rs746219926
• NM_031427.4:c.23_24delAA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_031427.4(DNAL1):​c.23_24delAA​(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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.31

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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. Fraction of 0.96 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: 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 rank	MANE	Protein	UniProt
DNAL1	NM_031427.4	c.23_24delAA	p.Lys8ArgfsTer16	frameshift_variant	Exon 2 of 8	ENST00000553645.7	NP_113615.2
DNAL1	NM_001201366.2	c.-95_-94delAA		5_prime_UTR_variant	Exon 3 of 9		NP_001188295.1
DNAL1	XM_017021679.3	c.-95_-94delAA		5_prime_UTR_variant	Exon 3 of 9		XP_016877168.1
DNAL1	XM_024449715.2	c.-95_-94delAA		5_prime_UTR_variant	Exon 3 of 9		XP_024305483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAL1	ENST00000553645.7	c.23_24delAA	p.Lys8ArgfsTer16	frameshift_variant	Exon 2 of 8	1	NM_031427.4	ENSP00000452037.1

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 150206 Hom.: 0 Cov.: 31

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 AF: 0.0000200 AC: 3 AN: 150314 Hom.: 0 Cov.: 31 AF XY: 0.0000137 AC XY: 1 AN XY: 73252

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

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Dec 11, 2023

Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

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

Other links and lift over

dbSNP: rs746219926; hg19: chr14-74121567;