rs755136231

chr5-13791994-ATTTGGTTC-A

Variant summary

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

The NM_001369.3(DNAH5):c.8440_8447del(p.Glu2814Ter) 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:8

Conservation

PhyloP100: 4.27

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 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 5-13791994-ATTTGGTTC-A is Pathogenic according to our data. Variant chr5-13791994-ATTTGGTTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 454808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.8440_8447del	p.Glu2814Ter	frameshift_variant, splice_region_variant	50/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.8440_8447del	p.Glu2814Ter	frameshift_variant, splice_region_variant	50/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.8395_8402del	p.Glu2799Ter	frameshift_variant, splice_region_variant	50/79			A1

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

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250882

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135640

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	Dec 11, 2023	ACMG: PVS1, PM2, PM3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Mar 13, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	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.Glu2814fs1. ClinVar contains an entry for this variant (Variation ID: 454808). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 13, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Primary ciliary dyskinesia 3

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 05, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 02, 2021	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 29, 2022

PVS1, PP4, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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