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rs755136231

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]

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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
DNAH5NM_001369.3 linkuse as main transcriptc.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
DNAH5ENST00000265104.5 linkuse as main transcriptc.8440_8447del p.Glu2814Ter frameshift_variant, splice_region_variant 50/791 NM_001369.3 P4
DNAH5ENST00000681290.1 linkuse as main transcriptc.8395_8402del p.Glu2799Ter frameshift_variant, splice_region_variant 50/79 A1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152214
Hom.:
0
Cov.:
33
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:
5
AN:
250882
Hom.:
0
AF XY:
0.0000295
AC XY:
4
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:
25
AN:
1459854
Hom.:
0
AF XY:
0.0000193
AC XY:
14
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:
2
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
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 submitterclinical testingAmbry GeneticsJan 13, 2022The 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, criteria provided, single submitterclinical testingUNC Molecular Genetics Laboratory, University of North Carolina at Chapel HillMar 13, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 06, 2023This 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. -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingInstitute Of Molecular Biology And Genetics, Federal Almazov National Medical Research CentreDec 11, 2023ACMG: PVS1, PM2, PM3, PP5 -
Primary ciliary dyskinesia 3 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsNov 02, 2021- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 05, 2018The 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. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenAug 29, 2022PVS1, 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.

Other links and lift over

dbSNP: rs755136231; hg19: chr5-13792103; API