rs876657683

Positions:

• chr9-34489393-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_012144.4(DNAI1):​c.336del​(p.Asp114ThrfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I111I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DNAI1 NM_012144.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.0600

Genes affected

DNAI1 (HGNC:2954): (dynein axonemal intermediate chain 1) This gene encodes a member of the dynein intermediate chain family. The encoded protein is part of the dynein complex in respiratory cilia. The inner- and outer-arm dyneins, which bridge between the doublet microtubules in axonemes, are the force-generating proteins responsible for the sliding movement in axonemes. The intermediate and light chains, thought to form the base of the dynein arm, help mediate attachment and may also participate in regulating dynein activity. Mutations in this gene result in abnormal ciliary ultrastructure and function associated with primary ciliary dyskinesia and Kartagener syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Pathogenic. Variant got 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 9-34489393-TC-T is Pathogenic according to our data. Variant chr9-34489393-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 228334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI1	NM_012144.4	c.336del	p.Asp114ThrfsTer14	frameshift_variant	5/20	ENST00000242317.9
DNAI1	NM_001281428.2	c.336del	p.Asp114ThrfsTer14	frameshift_variant	5/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9	c.336del	p.Asp114ThrfsTer14	frameshift_variant	5/20	1	NM_012144.4
DNAI1	ENST00000614641.4	c.336del	p.Asp114ThrfsTer14	frameshift_variant	5/20	5		P1
DNAI1	ENST00000437363.5	c.303del	p.Asp103ThrfsTer14	frameshift_variant	4/9	5
DNAI1	ENST00000488369.1	n.452del		non_coding_transcript_exon_variant	5/9	3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00000479 AC: 7 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74294

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

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: 0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 20, 2023	This sequence change creates a premature translational stop signal (p.Asp114Thrfs*14) in the DNAI1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAI1 are known to be pathogenic (PMID: 16858015, 29363216). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DNAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228334). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 29, 2019	The c.336delC pathogenic mutation, located in coding exon 5 of the DNAI1 gene, results from a deletion of one nucleotide at nucleotide position 336, causing a translational frameshift with a predicted alternate stop codon (p.D114Tfs*14). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 27, 2016	The p.Asp114fs variant in DNAI1 has not been previously reported in individuals with primary ciliary dyskinesia or in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 114 and leads to a premature termination codon 14 amino ac ids downstream. This alteration is then predicted to lead to a truncated or abse nt protein. Homozygous and compound heterozygous loss of function variants in D NAI1 have been well documented in individuals with primary ciliary dyskinesia ac ross several studies and are rare in individuals from large population databases . In addition, an animal model study reveals that absence of Dnaic1 in mice lead s to a reduction of mucociliary clearance resulting in chronic rhinosinusitis, which supports loss of funtion as a disease mechanism (Ostrowski 2009). In summa ry, this variant meets our criteria to be classified as pathogenic for primary c iliary dyskinesia in an autosomal recessive manner (http://www.partners.org/per sonalizedmedicine/LMM) based upon its predicted impact on the protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs876657683; hg19: chr9-34489391;