rs760781678
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001206927.2(DNAH8):c.11531A>T(p.Asp3844Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,618 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 (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
DNAH8
NM_001206927.2 missense
NM_001206927.2 missense
Scores
6
6
3
Clinical Significance
Conservation
PhyloP100: 8.18
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 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.851
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH8 | NM_001206927.2 | c.11531A>T | p.Asp3844Val | missense_variant | 77/93 | ENST00000327475.11 | |
DNAH8-AS1 | NR_038401.1 | n.160+628T>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH8 | ENST00000327475.11 | c.11531A>T | p.Asp3844Val | missense_variant | 77/93 | 5 | NM_001206927.2 | P2 | |
DNAH8-AS1 | ENST00000416948.1 | n.152+628T>A | intron_variant, non_coding_transcript_variant | 2 | |||||
DNAH8 | ENST00000359357.7 | c.10880A>T | p.Asp3627Val | missense_variant | 75/91 | 2 | A2 | ||
DNAH8 | ENST00000449981.6 | c.11531A>T | p.Asp3844Val | missense_variant | 76/82 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250380Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135324
GnomAD3 exomes
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460618Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3AN XY: 726644
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
ExAC
?
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2
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2016 | In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs760781678, ExAC 0.02%) but has not been reported in the literature in individuals with a DNAH8-related disease. This sequence change replaces aspartic acid with valine at codon 3844 of the DNAH8 protein (Asp3844Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
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
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
REVEL
Uncertain
Polyphen
1.0
.;.;D
Vest4
MutPred
0.59
.;.;Loss of disorder (P = 0.0276);
MVP
MPC
0.69
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at