rs606231164

Variant names:

• chr9-34489343-T-TAATA
• rs606231164
• NM_012144.4:c.282_283insAATA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_012144.4(DNAI1):​c.282_283insAATA​(p.Gly95AsnfsTer24) 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 (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAI1 NM_012144.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.85
• 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: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 9-34489343-T-TAATA is Pathogenic according to our data. Variant chr9-34489343-T-TAATA is described in ClinVar as Pathogenic. ClinVar VariationId is 5605.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI1	NM_012144.4	c.282_283insAATA	p.Gly95AsnfsTer24	frameshift_variant	Exon 5 of 20	ENST00000242317.9	NP_036276.1
DNAI1	NM_001281428.2	c.282_283insAATA	p.Gly95AsnfsTer24	frameshift_variant	Exon 5 of 20		NP_001268357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAI1	ENST00000242317.9	c.282_283insAATA	p.Gly95AsnfsTer24	frameshift_variant	Exon 5 of 20	1	NM_012144.4	ENSP00000242317.4
DNAI1	ENST00000614641.4	c.282_283insAATA	p.Gly95AsnfsTer24	frameshift_variant	Exon 5 of 20	5		ENSP00000480538.1
DNAI1	ENST00000437363.5	c.249_250insAATA	p.Gly84AsnfsTer24	frameshift_variant	Exon 4 of 9	5		ENSP00000395396.1
DNAI1	ENST00000488369.1	n.398_399insAATA		non_coding_transcript_exon_variant	Exon 5 of 9	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Kartagener syndrome Pathogenic:1

Dec 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs606231164; hg19: chr9-34489341;