17-11598799-CTT-CT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001372.4(DNAH9):c.308delT(p.Phe103SerfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0006 in 1,479,728 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 1 hom. )

Consequence

DNAH9
NM_001372.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 2.46

Publications

0 publications found

Variant links:

Genes affected

DNAH9 (HGNC:2953): (dynein axonemal heavy chain 9) This gene encodes the heavy chain subunit of axonemal dynein, a large multi-subunit molecular motor. Axonemal dynein attaches to microtubules and hydrolyzes ATP to mediate the movement of cilia and flagella. The gene expresses at least two transcript variants; additional variants have been described, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

DNAH9 Gene-Disease associations (from GenCC):

ciliary dyskinesia, primary, 40
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
situs inversus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
schizophrenia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DNAH9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-11598799-CT-C is Pathogenic according to our data. Variant chr17-11598799-CT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1455970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH9	NM_001372.4 link	c.308delT	p.Phe103SerfsTer31	frameshift_variant	Exon 1 of 69	ENST00000262442.9	NP_001363.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DNAH9	ENST00000262442.9 link	c.308delT	p.Phe103SerfsTer31	frameshift_variant	Exon 1 of 69	1	NM_001372.4	ENSP00000262442.3
DNAH9	ENST00000579406.1 link	n.335delT		non_coding_transcript_exon_variant	Exon 1 of 8	1
DNAH9	ENST00000454412.6 link	c.308delT	p.Phe103SerfsTer31	frameshift_variant	Exon 1 of 68	5		ENSP00000414874.2
DNAH9	ENST00000579828.5 link	c.308delT	p.Phe103SerfsTer31	frameshift_variant	Exon 1 of 4	2		ENSP00000463782.1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000389

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000703

AC:

AN:

81052

AF XY:

0.000708

show subpopulations

Gnomad AFR exome

AF:

0.000991

Gnomad AMR exome

AF:

0.000438

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.000473

Gnomad FIN exome

AF:

0.000757

Gnomad NFE exome

AF:

0.00122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000614

AC:

815

AN:

1327512

Hom.:

Cov.:

AF XY:

0.000571

AC XY:

372

AN XY:

652050

show subpopulations

African (AFR)

AF:

0.000260

AC:

AN:

26890

American (AMR)

AF:

0.000396

AC:

AN:

27764

Ashkenazi Jewish (ASJ)

AF:

0.000400

AC:

AN:

22502

East Asian (EAS)

AF:

0.000295

AC:

AN:

30494

South Asian (SAS)

AF:

0.000334

AC:

AN:

74838

European-Finnish (FIN)

AF:

0.000175

AC:

AN:

34240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5084

European-Non Finnish (NFE)

AF:

0.000687

AC:

722

AN:

1050878

Other (OTH)

AF:

0.000474

AC:

AN:

54822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000480

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41558

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000390

AC:

AN:

5126

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000365

Hom.:

Bravo

AF:

0.000484

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ciliary dyskinesia, primary, 40

Pathogenic:3

Apr 02, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 04, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PVS1+PM3 -

DNAH9-related disorder

Pathogenic:1

Aug 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DNAH9 c.308delT variant is predicted to result in a frameshift and premature protein termination (p.Phe103Serfs*31). This variant was reported in the compound heterozygous state in an individual with laterality defects and congenital heart disease (described as c.302delT, Chen et al. 2022. PubMed ID: 35050399). This variant is reported in 0.10% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in DNAH9 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Phe103Serfs*31) in the DNAH9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH9 are known to be pathogenic (PMID: 30471718). This variant is present in population databases (rs769795916, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DNAH9-related conditions. ClinVar contains an entry for this variant (Variation ID: 1455970). For these reasons, this variant has been classified as Pathogenic. -

Primary ciliary dyskinesia

Uncertain:1

Sep 04, 2021

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=38/162

disease causing (fs/PTC)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over