rs76334696

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_012144.4(DNAI1):c.1604C>A(p.Thr535Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00654 in 1,614,238 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T535A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0076 ( 29 hom., cov: 32)

Exomes 𝑓: 0.0064 ( 249 hom. )

Consequence

DNAI1
NM_012144.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.67

Publications

10 publications found

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 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

DNAI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_012144.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0071043074).

BP6

Variant 9-34514428-C-A is Benign according to our data. Variant chr9-34514428-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012144.4. 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.1604C>A	p.Thr535Asn	missense	Exon 17 of 20	NP_036276.1	A0A140VJI0
	DNAI1	NM_001281428.2		c.1616C>A	p.Thr539Asn	missense	Exon 17 of 20	NP_001268357.1	A0A087WWV9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAI1	ENST00000242317.9	TSL:1 MANE Select	c.1604C>A	p.Thr535Asn	missense	Exon 17 of 20	ENSP00000242317.4	Q9UI46-1
DNAI1	ENST00000878474.1		c.1697C>A	p.Thr566Asn	missense	Exon 18 of 21	ENSP00000548533.1
DNAI1	ENST00000614641.4	TSL:5	c.1616C>A	p.Thr539Asn	missense	Exon 17 of 20	ENSP00000480538.1	A0A087WWV9

Frequencies

GnomAD3 genomes

AF:

0.00763

AC:

1162

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0643

Gnomad SAS

AF:

0.0480

Gnomad FIN

AF:

0.0432

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.0154

AC:

3861

AN:

251334

AF XY:

0.0168

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.0680

Gnomad FIN exome

AF:

0.0428

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.00643

AC:

9395

AN:

1461882

Hom.:

249

Cov.:

AF XY:

0.00771

AC XY:

5605

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.000425

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26136

East Asian (EAS)

AF:

0.0598

AC:

2375

AN:

39700

South Asian (SAS)

AF:

0.0453

AC:

3908

AN:

86258

European-Finnish (FIN)

AF:

0.0416

AC:

2220

AN:

53408

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000333

AC:

370

AN:

1112012

Other (OTH)

AF:

0.00782

AC:

472

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

655

1310

1965

2620

3275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00761

AC:

1160

AN:

152356

Hom.:

Cov.:

AF XY:

0.00985

AC XY:

734

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41584

American (AMR)

AF:

0.000980

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0642

AC:

333

AN:

5186

South Asian (SAS)

AF:

0.0480

AC:

232

AN:

4832

European-Finnish (FIN)

AF:

0.0432

AC:

459

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

68036

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

112

167

223

279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00350

Hom.:

Bravo

AF:

0.00343

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0152

AC:

1845

Asia WGS

AF:

0.0450

AC:

158

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (4)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

0.079

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.2

PhyloP100

1.7

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.18

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0040

Polyphen

0.0090

Vest4

0.18

MPC

0.20

ClinPred

0.029

GERP RS

4.6

Varity_R

0.46

gMVP

0.48

Mutation Taster

=81/19

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over