rs397515363

Variant names:

• chr9-34459054-G-GT
• rs397515363
• NM_012144.4:c.48+2dupT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Strong PS3 PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV004024533: This variant destroys a canonical donor site, is predicted to cause abnormal gene splicing and has supporting functional evidence." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (0 hom.)
• Consequence: DNAI1 ENST00000242317.9 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• Conservation: PhyloP100: 3.29
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004024533: This variant destroys a canonical donor site, is predicted to cause abnormal gene splicing and has supporting functional evidence.; SCV000289879: 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).; SCV000967664: Functional studies provide some evidence that this variant alters splicing, resulting in a truncated protein (Pennarun 1999, Zariwala 2006).; SCV001782235: Canonical splice site variant demonstrated to result in loss-of-function (Pennarun et al., 1999); SCV002072022: Functional studies showed that this 1-bp insertion impacts RNA splicing (PMID: 10577904).
• PP5: Variant 9-34459054-G-GT is Pathogenic according to our data. Variant chr9-34459054-G-GT is described in ClinVar as Pathogenic. ClinVar VariationId is 5604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000242317.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAI1	NM_012144.4	MANE Select	c.48+2dupT		splice_region intron	N/A	NP_036276.1	A0A140VJI0
	DNAI1	NM_001281428.2		c.48+2dupT		splice_region intron	N/A	NP_001268357.1	A0A087WWV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAI1	ENST00000242317.9	TSL:1 MANE Select	c.48+1_48+2insT		splice_donor intron	N/A	ENSP00000242317.4	Q9UI46-1
	DNAI1	ENST00000878474.1		c.48+1_48+2insT		splice_donor intron	N/A	ENSP00000548533.1
	DNAI1	ENST00000614641.4	TSL:5	c.48+1_48+2insT		splice_donor intron	N/A	ENSP00000480538.1	A0A087WWV9

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

GnomAD2 exomes AF: 0.000402 AC: 101 AN: 251308 AF XY: 0.000309

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 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

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000767 AC: 853 AN: 1111814

Other (OTH) AF: 0.000513 AC: 31 AN: 60394

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74470

African (AFR) AF: 0.000168 AC: 7 AN: 41564

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000679 Hom.: 0

Bravo AF: 0.000484

EpiCase AF: 0.000872

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	not provided (9)
7	-	-	Kartagener syndrome (8)
6	-	-	Primary ciliary dyskinesia (6)
1	-	-	DNAI1-related disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397515363; hg19: chr9-34459052; COSMIC: COSV52620044; COSMIC: COSV52620044;