rs148767488
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001206927.2(DNAH8):āc.5185A>Cā(p.Lys1729Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,613,418 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00022 ( 0 hom., cov: 32)
Exomes š: 0.00030 ( 0 hom. )
Consequence
DNAH8
NM_001206927.2 missense
NM_001206927.2 missense
Scores
5
3
7
Clinical Significance
Conservation
PhyloP100: 9.11
Genes affected
DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.35040247).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH8 | NM_001206927.2 | c.5185A>C | p.Lys1729Gln | missense_variant | 37/93 | ENST00000327475.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH8 | ENST00000327475.11 | c.5185A>C | p.Lys1729Gln | missense_variant | 37/93 | 5 | NM_001206927.2 | P2 | |
DNAH8 | ENST00000359357.7 | c.4534A>C | p.Lys1512Gln | missense_variant | 35/91 | 2 | A2 | ||
DNAH8 | ENST00000449981.6 | c.5185A>C | p.Lys1729Gln | missense_variant | 36/82 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000217 AC: 33AN: 152158Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000199 AC: 50AN: 250944Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135626
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GnomAD4 exome AF: 0.000296 AC: 433AN: 1461142Hom.: 0 Cov.: 30 AF XY: 0.000277 AC XY: 201AN XY: 726880
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GnomAD4 genome ? AF: 0.000217 AC: 33AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74454
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | Oct 12, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1729 of the DNAH8 protein (p.Lys1729Gln). This variant is present in population databases (rs148767488, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. ClinVar contains an entry for this variant (Variation ID: 407298). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C45"). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 18, 2022 | The c.5185A>C (p.K1729Q) alteration is located in exon 37 (coding exon 36) of the DNAH8 gene. This alteration results from a A to C substitution at nucleotide position 5185, causing the lysine (K) at amino acid position 1729 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
REVEL
Uncertain
Polyphen
1.0
.;.;D
Vest4
MVP
MPC
0.59
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