rs397515363

Positions:

• chr9-34459054-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_012144.4(DNAI1):​c.48+2dup variant causes a splice donor 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 NM_012144.4 splice_donor
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 3.29

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 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11809524 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/exons	MANE	Protein	UniProt
DNAI1	NM_012144.4	c.48+2dup		splice_donor_variant		ENST00000242317.9	NP_036276.1
DNAI1	NM_001281428.2	c.48+2dup		splice_donor_variant			NP_001268357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI1	ENST00000242317.9	c.48+2dup		splice_donor_variant		1	NM_012144.4	ENSP00000242317
DNAI1	ENST00000437363.5	c.48+2dup		splice_donor_variant		5		ENSP00000395396
DNAI1	ENST00000614641.4	c.48+2dup		splice_donor_variant		5		ENSP00000480538	P1
DNAI1	ENST00000470982.5	n.47+1595dup		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152182 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.000309 AC XY: 42 AN XY: 135854

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.: 0 Cov.: 30 AF XY: 0.000568 AC XY: 413 AN XY: 727118

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: 67 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74470

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.: 0

Bravo AF: 0.000484

EpiCase AF: 0.000872

EpiControl AF: 0.000533

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 28, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2022	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:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 02, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 22, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 21, 2022	ACMG classification criteria: PVS1 strong, PS3 supporting, PM2 moderated, PM3 very strong -

Primary ciliary dyskinesia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Oct 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	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 disrupted 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 introduces a premature termination codon (PMID: 10577904). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 09, 2018	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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2014

- -

DNAI1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2024

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

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

Other links and lift over

dbSNP: rs397515363; hg19: chr9-34459052;