rs748763552
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The ENST00000265104.5(DNAH5):āc.5290T>Cā(p.Ser1764Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,556,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 30)
Exomes š: 0.000021 ( 0 hom. )
Consequence
DNAH5
ENST00000265104.5 missense
ENST00000265104.5 missense
Scores
3
14
1
Clinical Significance
Conservation
PhyloP100: 5.49
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 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.863
PP5
Variant 5-13841886-A-G is Pathogenic according to our data. Variant chr5-13841886-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238980.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.5290T>C | p.Ser1764Pro | missense_variant | 33/79 | ENST00000265104.5 | NP_001360.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.5290T>C | p.Ser1764Pro | missense_variant | 33/79 | 1 | NM_001369.3 | ENSP00000265104 | P4 | |
DNAH5 | ENST00000681290.1 | c.5245T>C | p.Ser1749Pro | missense_variant | 33/79 | ENSP00000505288 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000203 AC: 3AN: 147786Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250766Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135692
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GnomAD4 exome AF: 0.0000213 AC: 30AN: 1408322Hom.: 0 Cov.: 29 AF XY: 0.0000171 AC XY: 12AN XY: 703518
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GnomAD4 genome AF: 0.0000203 AC: 3AN: 147786Hom.: 0 Cov.: 30 AF XY: 0.0000279 AC XY: 2AN XY: 71778
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2018 | The p.S1764P variant (also known as c.5290T>C), located in coding exon 33 of the DNAH5 gene, results from a T to C substitution at nucleotide position 5290. The serine at codon 1764 is replaced by proline, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 22, 2023 | This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1764 of the DNAH5 protein (p.Ser1764Pro). This variant is present in population databases (rs748763552, gnomAD 0.006%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (Invitae). ClinVar contains an entry for this variant (Variation ID: 238980). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAH5 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Primary ciliary dyskinesia 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 29, 2022 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
D
GERP RS
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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