rs137878131
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_001369.3(DNAH5):c.1715T>G(p.Leu572Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000637 in 1,604,074 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00075 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00063 ( 2 hom. )
Consequence
DNAH5
NM_001369.3 missense
NM_001369.3 missense
Scores
9
6
3
Clinical Significance
Conservation
PhyloP100: 6.93
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 -9 ACMG points.
BP6
Variant 5-13902068-A-C is Benign according to our data. Variant chr5-13902068-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 351208.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=8}.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000625 (908/1451726) while in subpopulation MID AF= 0.0098 (56/5712). AF 95% confidence interval is 0.00775. There are 2 homozygotes in gnomad4_exome. There are 486 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.1715T>G | p.Leu572Trp | missense_variant | 13/79 | ENST00000265104.5 | NP_001360.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.1715T>G | p.Leu572Trp | missense_variant | 13/79 | 1 | NM_001369.3 | ENSP00000265104 | P4 | |
DNAH5 | ENST00000681290.1 | c.1670T>G | p.Leu557Trp | missense_variant | 13/79 | ENSP00000505288 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000749 AC: 114AN: 152230Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000814 AC: 196AN: 240660Hom.: 0 AF XY: 0.000931 AC XY: 121AN XY: 129960
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GnomAD4 exome AF: 0.000625 AC: 908AN: 1451726Hom.: 2 Cov.: 29 AF XY: 0.000673 AC XY: 486AN XY: 721788
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GnomAD4 genome AF: 0.000748 AC: 114AN: 152348Hom.: 0 Cov.: 33 AF XY: 0.000792 AC XY: 59AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 3 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Sep 12, 2023 | The DNAH5 c.1715T>G (p.Leu572Trp) variant has been reported in one individual with Kartagener’s syndrome, but was not determined to be causative (Ozkavukcu S et al., PMID: 29402277). Additionally, DNAH5 c.1715T>G was published in an individual with situs inversus, but the protein change reported is p.Leu573*, so it is unclear if this is the same variant or a report of a distinct variant (Nöthe-Menchen T et al., PMID: 31638833). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.1% in the European (non-Finnish) population, which is consistent with carrier status of primary ciliary dyskinesia. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to DNAH5 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. - |
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 09, 2022 | - - |
Primary ciliary dyskinesia Uncertain:2Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 16, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2022 | This alteration is classified as likely 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 29, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | Oct 12, 2018 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2024 | Identified in a patient with primary ciliary dyskinesia in published literature, however additional genotype and phenotype information was not provided (Nothe-Menchen et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 35737725, 29402277, 31638833, 37860582) - |
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 22, 2018 | The p.Leu572Trp variant in DNAH5 has not been previously reported in individuals with primary ciliary dyskinesia, but has been identified in 0.1% (147/120780) o f European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs13787813). Computational prediction tools and conse rvation analysis suggest that the p.Leu572Trp variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, the clinical significance of the p.Leu572Trp variant is uncertain. ACMG/A MP Criteria applied: PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Uncertain
T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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