rs369137751
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001369.3(DNAH5):c.4807C>A(p.Pro1603Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,762 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00076 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 29 hom. )
Consequence
DNAH5
NM_001369.3 missense
NM_001369.3 missense
Scores
4
10
3
Clinical Significance
Conservation
PhyloP100: 7.90
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.015208662).
BP6
Variant 5-13859595-G-T is Benign according to our data. Variant chr5-13859595-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 525557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000756 (115/152210) while in subpopulation SAS AF= 0.0239 (115/4818). AF 95% confidence interval is 0.0203. There are 4 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.4807C>A | p.Pro1603Thr | missense_variant | 30/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.4807C>A | p.Pro1603Thr | missense_variant | 30/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.4762C>A | p.Pro1588Thr | missense_variant | 30/79 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000763 AC: 116AN: 152092Hom.: 4 Cov.: 32
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GnomAD3 exomes AF: 0.00239 AC: 601AN: 251366Hom.: 7 AF XY: 0.00321 AC XY: 436AN XY: 135854
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GnomAD4 exome AF: 0.00115 AC: 1684AN: 1461552Hom.: 29 Cov.: 32 AF XY: 0.00164 AC XY: 1195AN XY: 727116
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GnomAD4 genome AF: 0.000756 AC: 115AN: 152210Hom.: 4 Cov.: 32 AF XY: 0.00109 AC XY: 81AN XY: 74406
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2015 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2020 | See Variant Classification Assertion Criteria. - |
Primary ciliary dyskinesia 3 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
DNAH5-related disorder Benign:1
Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 04, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at