Variant 5-13841051-AT-ATT 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.5563_5564insA(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 (★★). 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.45

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 5-13841051-A-AT is Pathogenic according to our data. Variant chr5-13841051-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 407241.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.5563_5564insA	p.Ile1855AsnfsTer6	frameshift_variant	34/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.5563_5564insA	p.Ile1855AsnfsTer6	frameshift_variant	34/79	1	NM_001369.3	ENSP00000265104	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.5518_5519insA	p.Ile1840AsnfsTer6	frameshift_variant	34/79			ENSP00000505288	A1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251182

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135746

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000554

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000756

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 3

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Jan 25, 2022	ACMG categories: PVS1,PM3,PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Prenatal Genetic Diagnosis Laboratory, The Chinese University of Hong Kong	Mar 25, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 12, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP1,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 22, 2021	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. -

Primary ciliary dyskinesia

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 19, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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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