rs1060501178

chr14-73687374-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_031427.4(DNAL1):c.384del(p.Asp129ThrfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAL1 NM_031427.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.347

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 Pathogenic. Variant got 12 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 14-73687374-TA-T is Pathogenic according to our data. Variant chr14-73687374-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 406536.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAL1	NM_031427.4	c.384del	p.Asp129ThrfsTer6	frameshift_variant	6/8	ENST00000553645.7
DNAL1	NM_001201366.2	c.267del	p.Asp90ThrfsTer6	frameshift_variant	7/9
DNAL1	XM_017021679.3	c.267del	p.Asp90ThrfsTer6	frameshift_variant	7/9
DNAL1	XM_024449715.2	c.267del	p.Asp90ThrfsTer6	frameshift_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAL1	ENST00000553645.7	c.384del	p.Asp129ThrfsTer6	frameshift_variant	6/8	1	NM_031427.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 16 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

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). This sequence change creates a premature translational stop signal (p.Asp129Thrfs*6) 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). ClinVar contains an entry for this variant (Variation ID: 406536). 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)		0.11		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: rs1060501178; hg19: chr14-74154077;