Variant rs775696136 details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001369.3(DNAH5):c.13458_13459insT(p.Asn4487Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

DNAH5
NM_001369.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 1.69

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 5-13701316-T-TA is Pathogenic according to our data. Variant chr5-13701316-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 350995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.13458_13459insT	p.Asn4487Ter	frameshift_variant	77/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DNAH5	ENST00000265104.5 linkuse as main transcript	c.13458_13459insT	p.Asn4487Ter	frameshift_variant	77/79	1	NM_001369.3	ENSP00000265104	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.13413_13414insT	p.Asn4472Ter	frameshift_variant	77/79			ENSP00000505288	A1
DNAH5	ENST00000683611.1 linkuse as main transcript	n.791_792insT		non_coding_transcript_exon_variant	3/5

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251312

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

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:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000168

AC:

245

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

127

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

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:

0.000210

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000921

AC:

AN:

151966

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.0000967

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000791

Hom.:

Bravo

AF:

0.000136

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Nov 08, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.13458dupT (p.Asn4487Ter) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Asn4487Ter variant has been reported in one patient with primary ciliary dyskinesia in a homozygous state, and three patients in a compound heterozygous state with a second missense or frameshift variant (Hornef et al. 2006). Control data are unavailable for this variant, which is reported at a frequency of 0.00070 in the African American population of the Exome Sequencing Project. Based on the evidence and the potential impact of frameshift variants, the p.Asn4487Ter variant is classified as likely pathogenic for primary ciliary dyskinesia. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This sequence change creates a premature translational stop signal (p.Asn4487*) 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 (rs775696136, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16627867, 21270641). ClinVar contains an entry for this variant (Variation ID: 350995). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Centre for Genomic and Experimental Medicine, University of Edinburgh	Apr 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2020	The c.13458dupT pathogenic mutation (also known as p.N4487* and c.13458_13459insT), located in coding exon 77 of the DNAH5 gene, results from a duplication of T at nucleotide position 13458. This changes the amino acid from an asparagine to a stop codon within coding exon 77. This alteration was first identified in 4 families with PCD; it was detected in conjunction with another pathogenic mutation in 3 families and in the homozygous state in 1 family (Hornef N et al. Am. J. Respir. Crit. Care Med. 2006; 174:120-6). This alteration was also identified in conjunction with a deletion of exon 62 in a 16 year old female with PCD; this individual had a history of neonatal respiratory distress, situs inversus, bronchiectasis, sinusitis, frequent otitis media, significantly reduced nasal nitric oxide, and outer dyenin arm defects on electron microscopy (Berg JS et al. Genet. Med. 2011; 13:218-29). 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. -

Primary ciliary dyskinesia 3

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 18, 2019	This DNAH5 variant (rs775696136) has been identified in the homozgyous or compound heterozgygous state in multiple patients with primary ciliary dyskinesia. It is rare in population datasets (gnomAD: 16/251312 total alleles; 0.006367%; no homozygotes). Two submitters to ClinVar have classified DNAH5 c.13458dupT as either likely pathogenic or pathogenic. This frameshift variant results in a premature stop codon in exon 77 of 79 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Primary ciliary dyskinesia 3 (MIM#608644). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2; 16 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with primary ciliary dyskinesia, both homozygotes and compound heterozygotes (ClinVar, PMID: 33635012). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 20, 2021	The DNAH5 c.13458dupT; p.Asn4487Ter variant (rs775696136) is reported in the literature in the homozygous or compound heterozygous state in nine individuals affected with primary ciliary dyskinesia (Hornef 2006, Fassad 2020). This variant is also reported in ClinVar (Variation ID: 350995). This variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (13/113666 alleles) in the Genome Aggregation Database. This variant results in an early termination codon and is predicted to results in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Hornef N et al. DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. Am J Respir Crit Care Med. 2006 Jul 15;174(2):120-6. PMID: 16627867. Fassad MR et al. Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort. J Med Genet. 2020 May;57(5):322-330. PMID: 31879361. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2023	Nonsense 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: 31638833, 34791246, 34758253, 24498942, 31980526, 31589614, 33635012, 35753512, 21270641, 30293990, 16627867, 31879361) -

DNAH5-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2024

The DNAH5 c.13458dupT variant is predicted to result in premature protein termination (p.Asn4487*). This variant has been reported in the homozygous or compound heterozygous state in individuals with primary ciliary dyskinesia (see, for example, Hornef et al. 2006. PubMed ID: 16627867; Quinlan-Jones et al. 2018. PubMed ID: 30293990; Fassad et al. 2019. PubMed ID: 31879361). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. Nonsense 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

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

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