rs11999454

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012144.4(DNAI1):c.1460T>G(p.Val487Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0127 in 1,614,028 control chromosomes in the GnomAD database, including 846 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 139 hom., cov: 32)

Exomes 𝑓: 0.011 ( 707 hom. )

Consequence

DNAI1
NM_012144.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.84

Publications

11 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: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001478523).

BP6

Variant 9-34512395-T-G is Benign according to our data. Variant chr9-34512395-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI1	NM_012144.4 link	c.1460T>G	p.Val487Gly	missense_variant	Exon 15 of 20	ENST00000242317.9	NP_036276.1	Q9UI46-1A0A140VJI0
DNAI1	NM_001281428.2 link	c.1472T>G	p.Val491Gly	missense_variant	Exon 15 of 20		NP_001268357.1	Q9UI46A0A087WWV9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAI1	ENST00000242317.9 link	c.1460T>G	p.Val487Gly	missense_variant	Exon 15 of 20	1	NM_012144.4	ENSP00000242317.4	Q9UI46-1
DNAI1	ENST00000614641.4 link	c.1472T>G	p.Val491Gly	missense_variant	Exon 15 of 20	5		ENSP00000480538.1	A0A087WWV9
DNAI1	ENST00000470169.5 link	n.395T>G		non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000434296.1	H0YDT9

Frequencies

GnomAD3 genomes

AF:

0.0282

AC:

4294

AN:

152036

Hom.:

138

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0608

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0463

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.0274

Gnomad FIN

AF:

0.0125

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00159

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.0344

AC:

8656

AN:

251300

AF XY:

0.0290

show subpopulations

Gnomad AFR exome

AF:

0.0644

Gnomad AMR exome

AF:

0.110

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.131

Gnomad FIN exome

AF:

0.0137

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0110

AC:

16142

AN:

1461874

Hom.:

707

Cov.:

AF XY:

0.0107

AC XY:

7789

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0650

AC:

2175

AN:

33480

American (AMR)

AF:

0.102

AC:

4552

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00191

AC:

AN:

26136

East Asian (EAS)

AF:

0.113

AC:

4489

AN:

39696

South Asian (SAS)

AF:

0.0234

AC:

2014

AN:

86252

European-Finnish (FIN)

AF:

0.0121

AC:

649

AN:

53420

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00105

AC:

1163

AN:

1112008

Other (OTH)

AF:

0.0163

AC:

987

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1037

2074

3111

4148

5185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

256

512

768

1024

1280

<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:

0.0283

AC:

4310

AN:

152154

Hom.:

139

Cov.:

AF XY:

0.0290

AC XY:

2158

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0610

AC:

2532

AN:

41514

American (AMR)

AF:

0.0464

AC:

710

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.121

AC:

625

AN:

5174

South Asian (SAS)

AF:

0.0270

AC:

130

AN:

4822

European-Finnish (FIN)

AF:

0.0125

AC:

132

AN:

10582

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00159

AC:

108

AN:

67974

Other (OTH)

AF:

0.0260

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

204

408

611

815

1019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0140

Hom.:

172

Bravo

AF:

0.0363

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.0611

AC:

269

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.0328

AC:

3978

Asia WGS

AF:

0.0770

AC:

265

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:4

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val487Gly in exon 15 of DNAI1: This variant is not expected to have clinical sig nificance because it has been identified in 6.1% (269/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs11999454). -

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Kartagener syndrome

Benign:1

Mar 06, 2017

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0033

T;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.0042

LIST_S2

Benign

0.40

T;T

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.7

.;N

PhyloP100

3.8

PrimateAI

Benign

0.30

PROVEAN

Benign

4.3

.;N

REVEL

Benign

0.19

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.023

MPC

0.15

ClinPred

0.00073

GERP RS

3.5

Varity_R

0.042

gMVP

0.29

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over