rs758895180
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_015512.5(DNAH1):c.11074G>A(p.Glu3692Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000049 in 1,613,856 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 (★★).
Frequency
Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000044 ( 0 hom. )
Consequence
DNAH1
NM_015512.5 missense
NM_015512.5 missense
Scores
7
10
Clinical Significance
Conservation
PhyloP100: 6.80
Genes affected
DNAH1 (HGNC:2940): (dynein axonemal heavy chain 1) This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile. [provided by RefSeq, Feb 2017]
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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=0.39033183).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH1 | NM_015512.5 | c.11074G>A | p.Glu3692Lys | missense_variant | 69/78 | ENST00000420323.7 | |
DNAH1 | XM_017006129.2 | c.11143G>A | p.Glu3715Lys | missense_variant | 71/80 | ||
DNAH1 | XM_017006130.2 | c.11074G>A | p.Glu3692Lys | missense_variant | 70/79 | ||
DNAH1 | XM_017006131.2 | c.11017G>A | p.Glu3673Lys | missense_variant | 70/79 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH1 | ENST00000420323.7 | c.11074G>A | p.Glu3692Lys | missense_variant | 69/78 | 1 | NM_015512.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000804 AC: 20AN: 248898Hom.: 0 AF XY: 0.0000888 AC XY: 12AN XY: 135078
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GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461548Hom.: 0 Cov.: 32 AF XY: 0.0000536 AC XY: 39AN XY: 727044
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GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74480
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 27, 2023 | This variant has not been reported in the literature in individuals affected with DNAH1-related conditions. 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. 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 DNAH1 protein function. ClinVar contains an entry for this variant (Variation ID: 478395). This variant is present in population databases (rs758895180, gnomAD 0.05%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3692 of the DNAH1 protein (p.Glu3692Lys). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 22, 2023 | The c.11074G>A (p.E3692K) alteration is located in exon 69 (coding exon 68) of the DNAH1 gene. This alteration results from a G to A substitution at nucleotide position 11074, causing the glutamic acid (E) at amino acid position 3692 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Vest4
MutPred
Gain of MoRF binding (P = 0.0071);
MVP
MPC
ClinPred
D
GERP RS
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