chr17-11598799-C-CT

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001372.4(DNAH9):c.308dupT(p.Leu104ProfsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,479,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

DNAH9
NM_001372.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9U:2

Conservation

PhyloP100: 2.46

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-11598799-C-CT is Pathogenic according to our data. Variant chr17-11598799-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 523437.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.308dupT	p.Leu104ProfsTer45	frameshift_variant	Exon 1 of 69	ENST00000262442.9	NP_001363.2	Q9NYC9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH9	ENST00000262442.9 link	c.308dupT	p.Leu104ProfsTer45	frameshift_variant	Exon 1 of 69	1	NM_001372.4	ENSP00000262442.3	Q9NYC9-1
DNAH9	ENST00000579406.1 link	n.335dupT		non_coding_transcript_exon_variant	Exon 1 of 8	1
DNAH9	ENST00000454412.6 link	c.308dupT	p.Leu104ProfsTer45	frameshift_variant	Exon 1 of 68	5		ENSP00000414874.2	E7EP17
DNAH9	ENST00000579828.5 link	c.308dupT	p.Leu104ProfsTer45	frameshift_variant	Exon 1 of 4	2		ENSP00000463782.1	J3QQK8

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000333

AC:

AN:

81052

Hom.:

AF XY:

0.000322

AC XY:

AN XY:

46600

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000188

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000171

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000660

Gnomad OTH exome

AF:

0.000441

GnomAD4 exome

AF:

0.000506

AC:

672

AN:

1327572

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

333

AN XY:

652088

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.000311

Gnomad4 EAS exome

AF:

0.000197

Gnomad4 SAS exome

AF:

0.000214

Gnomad4 FIN exome

AF:

0.0000292

Gnomad4 NFE exome

AF:

0.000567

Gnomad4 OTH exome

AF:

0.000547

GnomAD4 genome

AF:

0.000309

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.000306

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ciliary dyskinesia, primary, 40

Pathogenic:4Uncertain:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PM3_Strong -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

This variant was classified as: Uncertain significance. This variant was inherited from a parent. -

Jul 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DNAH9 c.308dup; p.Leu104Profs variant (rs769795916; ClinVar Variation ID: 523437) is reported in the literature in multiple individuals who also carried an additional pathogenic variant in DNAH9, and who were primarily recruited for laterality defects, congenital heart defects, or otherwise suspected of having a primary ciliary dyskinesia (Chen 2022, De Jesus-Rojas 2023, Loges 2018, Miletic 2021). This variant is found in the general population with an overall allele frequency of 0.029% (32/112,330 alleles) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by inserting a single nucleotide in exon 1 (of 69), so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Chen W et al. Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease. Hum Genet. 2022 Aug;141(8):1339-1353. PMID: 35050399. De Jesus-Rojas W et al. The Genetics of Primary Ciliary Dyskinesia in Puerto Rico. Diagnostics (Basel). 2022 May 2;12(5):1127. PMID: 35626283. Loges NT et al. Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects. Am J Hum Genet. 2018 Dec 6;103(6):995-1008. PMID: 30471718. Miletic A et al. Genetic evaluation of newborns with critical congenital heart defects admitted to the intensive care unit. Eur J Pediatr. 2021 Oct;180(10):3219-3227. PMID: 33963417. -

Mar 30, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.028%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000523437 /PMID: 30471718). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAH9: PVS1, PM2 -

Jun 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30471718, 34426522, 33963417, 33610189) -

Jan 06, 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.Leu104Profs*45) 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 (rs773305837, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 30471718). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 523437). For these reasons, this variant has been classified as Pathogenic. -

Hydrocephalus

Pathogenic:1

Institute of Human Genetics, University of Wuerzburg

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

DNAH9-related disorder

Pathogenic:1

Aug 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DNAH9 c.308dupT variant is predicted to result in a frameshift and premature protein termination (p.Leu104Profs*45). This variant, along with other variants in DNAH9, has been reported in individuals with laterality defects and cardiac anomalies (Loges et al. 2018. PubMed ID: 30471718; Miletic et al. 2021. PubMed ID: 33963417; reported as c.302dupT, F6-II, Chen et al. 2022. PubMed ID: 35050399; De Jesús-Rojas et al. 2022. PubMed ID: 35626283). Of note, in one case the variant were confirmed to be in the compound heterozygous state (Miletic et al. 2021. PubMed ID: 33963417). This variant is reported in 0.052% 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. -

Abnormal cardiovascular system morphology

Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over