5-13841051-AT-ATT

Variant names:

• chr5-13841051-A-AT
• rs752925056
• NM_001369.3:c.5563dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001369.3(DNAH5):​c.5563dupA​(p.Ile1855AsnfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,974 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. I1855I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: DNAH5 NM_001369.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 1.45
• Publications: 11 publications found

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

ACMG classification

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 5-13841051-A-AT is Pathogenic according to our data. Variant chr5-13841051-A-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 407241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.5563dupA	p.Ile1855AsnfsTer6	frameshift	Exon 34 of 79	NP_001360.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.5563dupA	p.Ile1855AsnfsTer6	frameshift	Exon 34 of 79	ENSP00000265104.4
	DNAH5	ENST00000681290.1		c.5518dupA	p.Ile1840AsnfsTer6	frameshift	Exon 34 of 79	ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251182 AF XY: 0.0000663

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000616 AC: 90 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50 AN XY: 727216

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.000554 AC: 22 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111990

Other (OTH) AF: 0.0000993 AC: 6 AN: 60394

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.000131 AC: 2 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000756

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 3 Pathogenic:7

Oct 22, 2021

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAH5 c.5563dupA has been reported in multiple individuals with primary ciliary dyskinesia. This variant (rs752925056) is rare (<0.1%) in a large population dataset (gnomAD: 17/282580 total alleles; 0.006%; no homozygotes) and has been reported in ClinVar. This frameshift variant results in a premature stop codon in exon 34 likely leading to nonsense-mediated decay and lack of protein production. We consider DNAH5 c.5563dupA to be pathogenic.

Feb 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mar 12, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP1,PP3.

Apr 23, 2025

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 v4.1.0 dataset (total allele frequency: 0.006%). 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: VCV000407241 / PMID: 11788826). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Jan 25, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PM3,PP5

Mar 25, 2021

Prenatal Genetic Diagnosis Laboratory, The Chinese University of Hong Kong

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant c.5563dupA(p.I1855fs) creates a premature termination codon in exon 34, where nonsense-mediated decay is predicted to occur. The mechanism of pathogenicity in DNAH5 mutations appears to be bi-allelic loss of function [PMID: 16627867] (PVS1). This variant is extremely rare in the gnomAD database (PM2). It was previously reported in patients with primary ciliary dyskinesia and atrial and ventricular septal defects and found to be in trans configuration with another damaging variant or as a homozygote [PMID: 11788826, 28991257, 31118369, 31772028, 32622824] (PM3). It is interpreted as pathogenic according to ACMG/AMP guidelines.

May 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia Pathogenic:3

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.Ile1855Asnfs*6) 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 (rs752925056, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 11788826, 25186273, 26228299). ClinVar contains an entry for this variant (Variation ID: 407241). For these reasons, this variant has been classified as Pathogenic.

Sep 19, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5563dupA pathogenic mutation, located in coding exon 34 of the DNAH5 gene, results from a duplication of A at nucleotide position 5563, causing a translational frameshift with a predicted alternate stop codon (p.I1855Nfs*6). This alteration has been detected in the homozygous state, or in conjunction with another DNAH5 mutation, in multiple individuals with primary ciliary dyskinesia (Hornef N et al. Am J Respir Crit Care Med, 2006 Jul;174:120-6; Guo Z et al. J Pediatr, 2020 10;225:157-165.e5; Kurokawa A et al. Respir Investig, 2021 Jul;59:550-554; Blanchon S et al. J Med Genet, 2020 04;57:237-244; Raidt J et al. Eur Respir J, 2014 Dec;44:1579-88; Djakow J et al. Pediatr Pulmonol, 2016 May;51:498-509). In addition, this alteration has been found to cosegregate with disease in four affected homozygous siblings with consanguineous parentage (Olbrich H et al. Nat. Genet., 2002 Feb;30:143-4; Omran H et al. Am. J. Respir. Cell Mol. Biol., 2000 Nov;23:696-702). 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.

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:1

Apr 01, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed multiple times with a pathogenic or likely pathogenic variant on the opposite allele (in trans) and in the homozygous state in patients from different ethnic backgrounds with primary ciliary dyskinesia, with and without situs inversus and congenital heart defects (PMID: 11788826, 16627867, 25186273, 26228299, 28991257, 31638833, 31118369); 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; Also known as c.5563insA and c.5563_5564insA; This variant is associated with the following publications: (PMID: 36864285, 11788826, 16627867, 31638833, 31118369, 26228299, 17059358, 15750039, 25186273, 28991257, 31772028, 32622824, 31589614, 33577779, 35441720, 38041506)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs752925056; hg19: chr5-13841160; COSMIC: COSV54226931;