chr14-73654864-CAA-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 0 publications found

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: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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. There are 10 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 VariationId is 2671843.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031427.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAL1	NM_031427.4	MANE Select	c.23_24delAA	p.Lys8ArgfsTer16	frameshift	Exon 2 of 8	NP_113615.2	Q4LDG9-1
	DNAL1	NM_001201366.2		c.-95_-94delAA		5_prime_UTR	Exon 3 of 9	NP_001188295.1	Q4LDG9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAL1	ENST00000553645.7	TSL:1 MANE Select	c.23_24delAA	p.Lys8ArgfsTer16	frameshift	Exon 2 of 8	ENSP00000452037.1	Q4LDG9-1
	DNAL1	ENST00000554871.5	TSL:1	c.-95_-94delAA		5_prime_UTR	Exon 3 of 9	ENSP00000451834.1	Q4LDG9-3
	DNAL1	ENST00000893991.1		c.23_24delAA	p.Lys8ArgfsTer16	frameshift	Exon 2 of 7	ENSP00000564050.1

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

African (AFR) AF: 0.0000735 AC: 3 AN: 40838

American (AMR) AF: 0.00 AC: 0 AN: 15044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67714

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=19/181	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs746219926; hg19: chr14-74121567;