rs397515363

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The ENST00000242317.9(DNAI1):c.48+1_48+2insT variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 0 hom. )

Consequence

DNAI1
ENST00000242317.9 splice_donor, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 3.29

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11857143 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.6, offset of 6, new splice context is: aacGTacgc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-34459054-G-GT is Pathogenic according to our data. Variant chr9-34459054-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 5604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI1	NM_012144.4 link	c.48+2dupT		splice_region_variant, intron_variant	Intron 1 of 19	ENST00000242317.9	NP_036276.1	Q9UI46-1A0A140VJI0
DNAI1	NM_001281428.2 link	c.48+2dupT		splice_region_variant, intron_variant	Intron 1 of 19		NP_001268357.1	Q9UI46A0A087WWV9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAI1	ENST00000242317.9 link	c.48+1_48+2insT	splice_donor_variant, intron_variant	Intron 1 of 19	1	NM_012144.4	ENSP00000242317.4	Q9UI46-1
DNAI1	ENST00000614641.4 link	c.48+1_48+2insT	splice_donor_variant, intron_variant	Intron 1 of 19	5		ENSP00000480538.1	A0A087WWV9
DNAI1	ENST00000437363.5 link	c.48+1_48+2insT	splice_donor_variant, intron_variant	Intron 1 of 8	5		ENSP00000395396.1	Q5T8G8
DNAI1	ENST00000470982.5 link	n.47+1594_47+1595insT	intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000838

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000402

AC:

101

AN:

251308

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000739

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000620

AC:

906

AN:

1461610

Hom.:

Cov.:

AF XY:

0.000568

AC XY:

413

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000767

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.000440

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000679

Hom.:

Bravo

AF:

0.000484

EpiCase

AF:

0.000872

EpiControl

AF:

0.000533

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 26, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2021

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change has been described in the gnomAD database with a frequency of 0.073% in the non-Finnish European subpopulation (dbSNP rs1435805945). This sequence change has previously been described in several individuals with DNAI1-related primary ciliary dyskinesia in both homozygous and compound heterozygous state (PMIDs: 16858015, 33131162, 10577904, and 18434704). Functional studies showed that this 1-bp insertion impacts RNA splicing (PMID: 10577904. c.48+2dup is a common founder mutation in primary ciliary dyskinesia (PMID: 16858015) and is also reported with alternative nomenclatures such as c.48+2_48+3insT and IVS+2_3insT in the literature. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to result in loss-of-function (Pennarun et al., 1999) in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20301301, 23477994, 11231901, 10577904, 26918822, 29363216, 18434704, 30290127, 16858015, 31772028, 31879361, 31980526, 33131162, 33726816, 27535533) -

Kartagener syndrome

Pathogenic:6Other:1

May 22, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This DNAI1 canonical splice variant has been reported in many individuals with primary ciliary dyskinesia 1. This variant (rs1435805945) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 113/282694 total alleles; 0.04%; 1 homozygote), and has been reported in ClinVar4 (Variation ID 5604). This variant destroys a canonical donor site, is predicted to cause abnormal gene splicing and has supporting functional evidence. We consider c.48+2dup in DNAI1 to be pathogenic. -

Apr 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 14, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 strong, PS3 supporting, PM2 moderated, PM3 very strong -

Primary ciliary dyskinesia

Pathogenic:5

Oct 02, 2020

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.48+2dupT variant in DNAI1 is a well-known pathogenic founder variant (Zari wala 2006). It has been reported in >25 compound heterozygous or homozygous indi viduals with primary ciliary dyskinesia (PCD) with or without situs inversus (Ka rtagener syndrome) and segregated with disease in at least 2 affected relatives (Pennarun 1999, Guichard 2001, Zariwala 2006, Failly 2008, Li 2016, Paff 2018). This variant has been identified in 91/126580 European chromosomes, including on e homozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; dbSNP rs397515363). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicin g leading to an abnormal or absent protein. Functional studies provide some evid ence that this variant alters splicing, resulting in a truncated protein (Pennar un 1999, Zariwala 2006), and ultrastructural defects in the outer dynein arms we re observed in homozygous or compound heterozygous individuals (Guichard 2001, P aff 2018). In summary, this variant meets criteria to be classified as pathogeni c for primary ciliary dyskinesia in an autosomal recessive manner. ACMG/AMP Crit eria applied: PVS1_Strong, PM3_VeryStrong, PS3_Moderate, PP1. -

Aug 01, 2018

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 1 of the DNAI1 gene. It does not directly change the encoded amino acid sequence of the DNAI1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs755575751, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individuals with primary ciliary dyskinesia (PMID: 10577904, 11231901, 16858015, 18434704). This variant is also known as c.48+2_48+3insT and IVS+2_3insT. ClinVar contains an entry for this variant (Variation ID: 5604). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in partial retention of intron 1, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10577904). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Jun 06, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DNAI1-related disorder

Pathogenic:1

May 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DNAI1 c.48+2dupT variant is predicted to result in an intronic duplication. This variant is a well-documented founder variant and known cause of autosomal recessive primary ciliary dyskinesia (PCD) and Kartagener syndrome (Pennarun et al. 1999. PubMed ID: 10577904; Zariwala et al. 2006. PubMed ID: 16858015; Failly et al. 2008. PubMed ID: 18434704). In the literature, this variant is also reported as IVS1+2_3insT or c.48+2_48+3insT. This variant is reported in 0.073% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.92

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over