chr9-34459001-TTGAGA-T

Position:

• chr9-34459001-TTGAGA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong 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

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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. Fraction of 1 CDS is truncated, and there are 2 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 id is 2026405.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI1	NM_012144.4	c.-1_4delGATGA	p.Met1fs	frameshift_variant, start_lost	1/20	ENST00000242317.9	NP_036276.1
DNAI1	NM_012144.4	c.-1_4delGATGA		5_prime_UTR_variant	1/20	ENST00000242317.9	NP_036276.1
DNAI1	NM_001281428.2	c.-1_4delGATGA	p.Met1fs	frameshift_variant, start_lost	1/20		NP_001268357.1
DNAI1	NM_001281428.2	c.-1_4delGATGA		5_prime_UTR_variant	1/20		NP_001268357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI1	ENST00000242317.9	c.-1_4delGATGA	p.Met1fs	frameshift_variant, start_lost	1/20	1	NM_012144.4	ENSP00000242317.4
DNAI1	ENST00000242317	c.-1_4delGATGA		5_prime_UTR_variant	1/20	1	NM_012144.4	ENSP00000242317.4

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the DNAI1 mRNA. The next in-frame methionine is located at codon 178. This variant has not been reported in the literature in individuals affected with DNAI1-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DNAI1 protein in which other variant(s) (p.Arg124Cys) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-34458999;