Variant chr14-73654864-CAA-C details in Genebe, Genetics Data Aggregator

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_24delAA(p.Lys8fs) 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]

DNAL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
DNAL1	NM_031427.4 linkuse as main transcript	c.23_24delAA	p.Lys8fs	frameshift_variant	2/8	ENST00000553645.7	NP_113615.2	Q4LDG9-1
DNAL1	NM_001201366.2 linkuse as main transcript	c.-95_-94delAA		5_prime_UTR_variant	3/9		NP_001188295.1	Q4LDG9-3
DNAL1	XM_017021679.3 linkuse as main transcript	c.-95_-94delAA		5_prime_UTR_variant	3/9		XP_016877168.1	Q4LDG9-3
DNAL1	XM_024449715.2 linkuse as main transcript	c.-95_-94delAA		5_prime_UTR_variant	3/9		XP_024305483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAL1	ENST00000553645.7 linkuse as main transcript	c.23_24delAA	p.Lys8fs	frameshift_variant	2/8	1	NM_031427.4	ENSP00000452037.1		Q4LDG9-1

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

150206

Hom.:

Cov.:

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

AF:

0.0000200

AC:

AN:

150314

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

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 submitter

clinical testing

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

Dec 11, 2023

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over