rs200488444

Variant names:

• chr9-34490011-G-C
• rs200488444
• NM_012144.4:c.389-1G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

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:6 U:3 B:1
• Conservation: PhyloP100: 4.12

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 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	c.389-1G>C		splice_acceptor_variant, intron_variant	Intron 5 of 19	ENST00000242317.9	NP_036276.1
DNAI1	NM_001281428.2	c.400G>C	p.Gly134Arg	missense_variant	Exon 6 of 20		NP_001268357.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152196 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.000390 AC XY: 53 AN XY: 135758

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.: 0 Cov.: 32 AF XY: 0.000312 AC XY: 227 AN XY: 727160

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: 69 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74490

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.: 1

Bravo AF: 0.000446

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000491

EpiControl AF: 0.000712

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Kartagener syndrome Pathogenic:3 Uncertain:2

Jan 25, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Pathogenic:1 Uncertain:1 Benign:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 25, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.92	D
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

Other links and lift over

dbSNP: rs200488444; hg19: chr9-34490009; COSMIC: COSV54282395; COSMIC: COSV54282395;