rs142036266
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6
The NM_001369.3(DNAH5):c.13778C>T(p.Thr4593Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000070 ( 0 hom. )
Consequence
DNAH5
NM_001369.3 missense
NM_001369.3 missense
Scores
6
5
7
Clinical Significance
Conservation
PhyloP100: 8.13
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 Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35422993).
BP6
Variant 5-13692081-G-A is Benign according to our data. Variant chr5-13692081-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219653.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.13778C>T | p.Thr4593Met | missense_variant | 79/79 | ENST00000265104.5 | NP_001360.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.13778C>T | p.Thr4593Met | missense_variant | 79/79 | 1 | NM_001369.3 | ENSP00000265104 | P4 | |
DNAH5 | ENST00000681290.1 | c.13733C>T | p.Thr4578Met | missense_variant | 79/79 | ENSP00000505288 | A1 | |||
DNAH5 | ENST00000683611.1 | n.1111C>T | non_coding_transcript_exon_variant | 5/5 |
Frequencies
GnomAD3 genomes AF: 0.000355 AC: 54AN: 152142Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000120 AC: 30AN: 250608Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135438
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GnomAD4 exome AF: 0.0000698 AC: 102AN: 1461800Hom.: 0 Cov.: 30 AF XY: 0.0000688 AC XY: 50AN XY: 727202
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GnomAD4 genome AF: 0.000355 AC: 54AN: 152260Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74456
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2024 | 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: 38206729, 34962988) - |
Primary ciliary dyskinesia 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
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