chr9-34459001-TTGAGA-T

Variant names:

• chr9-34459001-TTGAGA-T
• NM_012144.4:c.-1_4delGATGA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_012144.4(DNAI1):​c.-1_4delGATGA​(p.Met1fs) variant causes a frameshift, start lost 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAI1 NM_012144.4 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.66
• Publications: 0 publications found

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]

DNAI1 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 108 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-34459001-TTGAGA-T is Pathogenic according to our data. Variant chr9-34459001-TTGAGA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2026405.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012144.4. 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
	DNAI1	NM_012144.4	MANE Select	c.-1_4delGATGA	p.Met1fs	frameshift start_lost	Exon 1 of 20	NP_036276.1	A0A140VJI0
	DNAI1	NM_012144.4	MANE Select	c.-1_4delGATGA		5_prime_UTR	Exon 1 of 20	NP_036276.1	A0A140VJI0
	DNAI1	NM_001281428.2		c.-1_4delGATGA	p.Met1fs	frameshift start_lost	Exon 1 of 20	NP_001268357.1	A0A087WWV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAI1	ENST00000242317.9	TSL:1 MANE Select	c.-1_4delGATGA	p.Met1fs	frameshift start_lost	Exon 1 of 20	ENSP00000242317.4	Q9UI46-1
	DNAI1	ENST00000242317.9	TSL:1 MANE Select	c.-1_4delGATGA		5_prime_UTR	Exon 1 of 20	ENSP00000242317.4	Q9UI46-1
	DNAI1	ENST00000878474.1		c.-1_4delGATGA	p.Met1fs	frameshift start_lost	Exon 1 of 21	ENSP00000548533.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

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		2.7

Splicing

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

Other links and lift over

hg19: chr9-34458999;