rs369931315
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001369.3(DNAH5):āc.8956T>Cā(p.Tyr2986His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,612,730 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 Uncertain significance (ā ).
Frequency
Genomes: š 0.000053 ( 0 hom., cov: 32)
Exomes š: 0.00011 ( 0 hom. )
Consequence
DNAH5
NM_001369.3 missense
NM_001369.3 missense
Scores
12
4
2
Clinical Significance
Conservation
PhyloP100: 9.21
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 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.883
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.8956T>C | p.Tyr2986His | missense_variant | 54/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.8956T>C | p.Tyr2986His | missense_variant | 54/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.8911T>C | p.Tyr2971His | missense_variant | 54/79 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152224Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000116 AC: 29AN: 250140Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135178
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GnomAD4 exome AF: 0.000109 AC: 159AN: 1460506Hom.: 0 Cov.: 31 AF XY: 0.000100 AC XY: 73AN XY: 726564
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74382
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 2986 of the DNAH5 protein (p.Tyr2986His). This variant is present in population databases (rs369931315, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DNAH5-related conditions. ClinVar contains an entry for this variant (Variation ID: 454814). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
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