rs200488444

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_012144.4(DNAI1):c.389-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000345 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

DNAI1
NM_012144.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:3B:1

Conservation

PhyloP100: 4.12

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 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.7, offset of 8, new splice context is: tatcctaccaacgttctcAGgag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI1	NM_012144.4 link	c.389-1G>C		splice_acceptor_variant, intron_variant	Intron 5 of 19	ENST00000242317.9	NP_036276.1	Q9UI46-1A0A140VJI0
DNAI1	NM_001281428.2 link	c.400G>C	p.Gly134Arg	missense_variant	Exon 6 of 20		NP_001268357.1	Q9UI46A0A087WWV9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAI1	ENST00000242317.9 link	c.389-1G>C		splice_acceptor_variant, intron_variant	Intron 5 of 19	1	NM_012144.4	ENSP00000242317.4	Q9UI46-1
DNAI1	ENST00000614641.4 link	c.400G>C	p.Gly134Arg	missense_variant	Exon 6 of 20	5		ENSP00000480538.1	A0A087WWV9
DNAI1	ENST00000437363.5 link	c.356-1G>C		splice_acceptor_variant, intron_variant	Intron 4 of 8	5		ENSP00000395396.1	Q5T8G8
DNAI1	ENST00000488369.1 link	n.505-1G>C		splice_acceptor_variant, intron_variant	Intron 5 of 8	3

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000414

AC:

104

AN:

251146

Hom.:

AF XY:

0.000390

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000695

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000423

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000334

AC:

488

AN:

1461740

Hom.:

Cov.:

AF XY:

0.000312

AC XY:

227

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00233

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000315

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000453

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000506

Hom.:

Bravo

AF:

0.000446

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000428

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000712

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Kartagener syndrome

Pathogenic:3Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 23, 2018	The DNAI1 c.389-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. The variant is reported at a frequency of 0.00246 in the Ashkenazi Jewish population from the Genome Aggregation Database and includes one homozygous individual. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for primary ciliary dyskinesia.This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 19, 2024	- -

Primary ciliary dyskinesia

Pathogenic:1Uncertain:1Benign:1

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 18, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 04, 2024	The c.389-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 6 of the DNAI1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay; however, direct evidence is unavailable. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2024

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Observed in a patient with severe bronchiectasis; however, no second variant in this gene was identified (PMID: 35728977); This variant is associated with the following publications: (PMID: 34426522, 31589614, 28152038, 35728977) -

DNAI1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2024

The DNAI1 c.389-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature in association with disease. This variant is reported in 0.24% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Variants that disrupt the AG acceptor site have been reported to be pathogenic for primary ciliary dyskinesia (Zariwala et al. 2006. PubMed ID: 16858015), and this variant has been classified as likely pathogenic by multiple independent submitters and uncertain by one submitter to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/454836). Given the evidence, we interpret c.389-1G>C as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.92

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

SpliceAI score (max)

0.68

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.68

Position offset: 9

DS_AL_spliceai

0.36

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