rs200488444

chr9-34490011-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PM2 PP3_Strong

The NM_012144.4(DNAI1):c.389-1G>C variant causes a splice acceptor 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2 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 14 ACMG points.

• PVS1: Splicing 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI1	NM_012144.4	c.389-1G>C		splice_acceptor_variant		ENST00000242317.9
DNAI1	NM_001281428.2	c.400G>C	p.Gly134Arg	missense_variant	6/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9	c.389-1G>C		splice_acceptor_variant		1	NM_012144.4
DNAI1	ENST00000437363.5	c.356-1G>C		splice_acceptor_variant		5
DNAI1	ENST00000614641.4	c.400G>C	p.Gly134Arg	missense_variant	6/20	5		P1
DNAI1	ENST00000488369.1	n.505-1G>C		splice_acceptor_variant, non_coding_transcript_variant		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:5 Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Kartagener syndrome Pathogenic:2 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2017	- -
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	Revvity Omics, Revvity	Jan 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 17, 2022	- -

Primary ciliary dyskinesia Pathogenic:2 Benign:1

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2019	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. Using the ESEfinder and Human Splicing Finder (HSF) splice site prediction tools, this alteration is predicted to abolish or weaken the native splice acceptor site; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). 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. As such, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2019

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Reported in the published literature (LaDuca et al., 2017) without clinical information, segregation evidence, or evidence in support of pathogenicity provided; This variant is associated with the following publications: (PMID: 31589614, 28152038) -

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
MutationTaster	Benign	1.0	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;