GeneBe

rs397515540

Variant names:

Variant summary

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

The NM_001369.3(DNAH5):​c.10815delT​(p.Pro3606HisfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,613,778 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 0.00019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

DNAH5
NM_001369.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 0.172
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]

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 5-13753289-GA-G is Pathogenic according to our data. Variant chr5-13753289-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 65636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13753289-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAH5NM_001369.3 linkc.10815delT p.Pro3606HisfsTer23 frameshift_variant Exon 63 of 79 ENST00000265104.5 NP_001360.1 Q8TE73

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAH5ENST00000265104.5 linkc.10815delT p.Pro3606HisfsTer23 frameshift_variant Exon 63 of 79 1 NM_001369.3 ENSP00000265104.4 Q8TE73
DNAH5ENST00000681290.1 linkc.10770delT p.Pro3591HisfsTer23 frameshift_variant Exon 63 of 79 ENSP00000505288.1 A0A7P0Z455

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000382
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000163
AC:
41
AN:
250906
Hom.:
1
AF XY:
0.000155
AC XY:
21
AN XY:
135630
show subpopulations
Gnomad AFR exome
AF:
0.000123
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:
0.000344
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000434
AC:
635
AN:
1461660
Hom.:
0
Cov.:
31
AF XY:
0.000417
AC XY:
303
AN XY:
727134
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
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:
0.0000374
Gnomad4 NFE exome
AF:
0.000550
Gnomad4 OTH exome
AF:
0.000315
GnomAD4 genome
AF:
0.000191
AC:
29
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.000382
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000304
Hom.:
0
Bravo
AF:
0.000155
EpiCase
AF:
0.000436
EpiControl
AF:
0.000415

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:20Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 3 Pathogenic:9Other:1
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Feb 02, 2022
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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, with or without situs inversus (PCD; 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: 45 heterozygotes, 1 homozygote). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple families with primary ciliary dyskinesia (ClinVar, LOVD, PMIDs: 29363216, 16627867, 23477994). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 23, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 06, 2022
Johns Hopkins Genomics, Johns Hopkins University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

c.10815delT in DNAH5 has been identified in multiple unrelated individuals as well as families with primary ciliary dyskinesia and is a known North American founder mutation. This frameshift variant (rs397515540) has been reported in ClinVar (Variation ID 65636) and is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 47/282304 total alleles; 0.0167%; 1 homozygote). This frameshift variant results in a premature stop codon in exon 64 of 79, likely leading to nonsense-mediated decay and lack of protein production. We consider c.10815delT; p.Pro3606fs in DNAH5 to be pathogenic. -

Oct 17, 2016
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The DNAH5 c.10815delT (p.Pro3606HisfsTer23) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Pro3606HisfsTer23 variant has been reported in a total of 17 individuals with primary ciliary dyskinesia, including in two in a homozygous state and in 15 in a compound heterozygous state (Hornef et al. 2006; Djakow et al. 2012; Ferkol et al. 2013; Kim et al. 2014; Raidt et al. 2014). The p.Pro3606HisfsTer23 variant was found to segregate with disease where familial DNA was available, and haplotype analysis revealed this variant is a founder mutation (Hornef et al. 2006). The p.Pro3606HisfsTer23 variant was absent from 70 controls and is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of frameshift variants, the p.Pro3606HisfsTer23 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. -

-
Genomics England Pilot Project, Genomics England
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 13, 2020
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PM3, PP5 -

Mar 26, 2020
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

ACMG codes: PVS1, PM3, PP4, PP5 -

Feb 19, 2020
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 15, 2006
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Primary ciliary dyskinesia Pathogenic:7
Apr 01, 2020
Centre for Genomic and Experimental Medicine, University of Edinburgh
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Dec 11, 2023
Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG: PVS1, PM2, PM3, PP5 -

Dec 06, 2021
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.10815delT pathogenic mutation, located in coding exon 63 of the DNAH5 gene, results from a deletion of one nucleotide at nucleotide position 10815, causing a translational frameshift with a predicted alternate stop codon (p.P3606Hfs*23). In one study, this mutation was seen in 7 of 134 (5.2%) primary ciliary dyskinesia (PCD) families, with a particularly high prevalence in individuals with PCD from the United States (Hornef N et al. Am. J. Respir. Crit. Care Med., 2006 Jul;174:120-6). 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. -

Oct 25, 2024
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.Pro3606Hisfs*23) 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 (rs397515540, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16627867, 22416021, 23477994, 24498942). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65636). For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 01, 2018
Yale Center for Mendelian Genomics, Yale University
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Feb 05, 2024
Molecular Genetics, Royal Melbourne Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change in DNAH5 is a frameshift variant predicted to cause a premature stop codon, p.(Pro3606Hisfs*23), in biologically relevant exon 64/79 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.05% (638/1,179,900 alleles) in the European (non-Finnish) population. This variant is a North American founder mutation that has been detected in the homozygous and compound heterozygous state in multiple individuals with primary ciliary dyskinesia (PCD), confirmed in trans in at least one individual (PMID: 16627867, 29363216). It segregates with PCD in at least one family (PMID: 16627867). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PP1. -

not provided Pathogenic:4
May 27, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 03, 2017
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 20, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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; This variant is associated with the following publications: (PMID: 24498942, 16627867, 20301301, 28832562, 28991257, 23477994, 22416021, 29453417, 25186273, 31772028, 31879361, 31980526, 32111882, 31589614, 33726816) -

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.

Other links and lift over

dbSNP: rs397515540; hg19: chr5-13753398; API