rs876657637

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_031427.4(DNAL1):c.224_230delTATCTTT(p.Leu75fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000201 in 1,492,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

DNAL1
NM_031427.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 5.17

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 16
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-73671555-ATTATCTT-A is Pathogenic according to our data. Variant chr14-73671555-ATTATCTT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 228252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAL1	NM_031427.4 link	c.224_230delTATCTTT	p.Leu75fs	frameshift_variant	Exon 5 of 8	ENST00000553645.7	NP_113615.2	Q4LDG9-1
DNAL1	NM_001201366.2 link	c.107_113delTATCTTT	p.Leu36fs	frameshift_variant	Exon 6 of 9		NP_001188295.1	Q4LDG9-3
DNAL1	XM_017021679.3 link	c.107_113delTATCTTT	p.Leu36fs	frameshift_variant	Exon 6 of 9		XP_016877168.1	Q4LDG9-3
DNAL1	XM_024449715.2 link	c.107_113delTATCTTT	p.Leu36fs	frameshift_variant	Exon 6 of 9		XP_024305483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAL1	ENST00000553645.7 link	c.224_230delTATCTTT	p.Leu75fs	frameshift_variant	Exon 5 of 8	1	NM_031427.4	ENSP00000452037.1		Q4LDG9-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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

GnomAD4 exome

AF:

7.46e-7

AC:

AN:

1340554

Hom.:

AF XY:

0.00000151

AC XY:

AN XY:

663860

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28542

American (AMR)

AF:

0.00

AC:

AN:

29686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23110

East Asian (EAS)

AF:

0.00

AC:

AN:

35674

South Asian (SAS)

AF:

0.00

AC:

AN:

65698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5352

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1047856

Other (OTH)

AF:

0.0000182

AC:

AN:

54916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 16

Pathogenic:1

Mar 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Leu75*) in the DNAL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAL1 are known to be pathogenic (PMID: 21496787). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 228252). This variant has not been reported in the literature in individuals affected with DNAL1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Primary ciliary dyskinesia

Pathogenic:1

Feb 03, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Leu36X variant in DNAL1 has not been previously reported in individuals wi th pulmonary disease or in large population studies. This variant is a deletion of 7 nucleotides at position 107 and is predicted to alter the protein reading-f rame, resulting in a premature termination codon at amino acid position 36. This alteration is then predicted to lead to a truncated or absent protein. In summa ry, although additional studies are required to fully establish its clinical sig nificance, the p.Leu36X variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.2

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over