rs755136231

Variant names:

Variant summary

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

The NM_001369.3(DNAH5):c.8440_8447delGAACCAAA(p.Glu2814fs) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.0000167 in 1,612,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E2814E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

DNAH5
NM_001369.3 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.27

Publications

4 publications found

Variant links:

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

DNAH5 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAH5 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 5-13791994-ATTTGGTTC-A is Pathogenic according to our data. Variant chr5-13791994-ATTTGGTTC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 454808.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
DNAH5	NM_001369.3 link	c.8440_8447delGAACCAAA	p.Glu2814fs	frameshift_variant, splice_region_variant	Exon 50 of 79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 link	c.8440_8447delGAACCAAA	p.Glu2814fs	frameshift_variant, splice_region_variant	Exon 50 of 79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1 link	c.8395_8402delGAACCAAA	p.Glu2799fs	frameshift_variant, splice_region_variant	Exon 50 of 79			ENSP00000505288.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

250882

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1459854

Hom.:

AF XY:

0.0000193

AC XY:

AN XY:

726390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1110388

Other (OTH)

AF:

0.0000166

AC:

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:5

Mar 13, 2019

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.8440_8447delGAACCAAA pathogenic mutation, located in coding exon 50 of the DNAH5 gene, results from a deletion of 8 nucleotides at nucleotide positions 8440 to 8447, causing a translational frameshift with a predicted alternate stop codon (p.E2814*). This mutation, also referred to as 2814fsX1, was described as homozygous in an individual whose respiratory cilia showed absence of outer dynein arms under electron microscopy analysis (Olbrich H et al, Nat. Genet. 2002 Feb; 30(2):143-4). Subsequent immunofluorescent studies of this individual's respiratory epithelial cells suggested that this alteration lead to protein mislocalization (Fliegauf M et al, Am. J. Respir. Crit. Care Med. 2005 Jun; 171(12):1343-9). This alteration was also identified in trans with a pathogenic DNAH5 mutation (p.R3539H) in an individual with a similar absence of outer dynein arms (Djakow J et al. Pediatr Pulmonol, 2012 Sep;47:864-75). Additionally, this variant was detected in an individual who had another frameshift mutation (c.10815delT) and showed abnormal ciliary beat patterns (Raidt J et al, Eur. Respir. J. 2014 Dec; 44(6):1579-88), as well as in an individual with inner dynein arm and outer dynein arm defects who had a DNAH5 nonsense mutation (p.R2677*) along with the c.8440_8447delGAACCAAA mutation (Djakow J et al. Pediatr Pulmonol, 2016 May;51:498-509). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Jan 29, 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.Glu2814*) in the DNAH5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). This variant is present in population databases (rs755136231, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 11788826, 16627867, 22416021, 25186273). This variant is also known as p.Glu2814fs*1. ClinVar contains an entry for this variant (Variation ID: 454808). For these reasons, this variant has been classified as Pathogenic. -

Dec 11, 2023

Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG: PVS1, PM2, PM3, PP5 -

not provided

Pathogenic:2

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNAH5: PVS1, PM2 -

Aug 29, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PP4, PM2_SUP -

Primary ciliary dyskinesia 3

Pathogenic:2

Mar 05, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DNAH5 c.8440_8447delGAACCAAA (p.Glu2814Ter) frameshift variant has been reported in five individuals with primary ciliary dyskinesia, including in one who carried the variant in a homozygous state, in three who carried the variant in a compound heterozygous state, and in one who carried the variant in a heterozygous state where a second variant was not identified, and also in a heterozygous state in an unaffected parent of a patient (Olbrich et al. 2002; Hornef et al, 2006; Djakow et al. 2012; Raidt et al. 2014; Djakow et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000063 in the European (non-Finnish) population from the Genome Aggregation Database. In respiratory epithelial cilia from an individual homozygous for the p.Glu2814Ter variant, expression of DNAH5 was observed at the ciliary base and the cilia were immotile, whereas expression of DNAH5 in controls was observed along the entire length of the axoneme (Fliegauf et al. 2005). Based on the evidence and due to the potential impact of frameshift variants, the p.Glu2814Ter variant is classified as pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Nov 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DNAH5-related disorder

Pathogenic:1

May 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DNAH5 c.8440_8447del8 variant is predicted to result in premature protein termination (p.Glu2814*). This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with primary ciliary dyskinesia (Olbrich et al. 2002. PubMed ID: 11788826; Table E2, Similuk et al. 2022. PubMed ID: 35753512; Raidt et al. 2014. PubMed ID: 25186273; Djakow et al. 2012. PubMed ID: 22416021). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in DNAH5 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.3

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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