rs374798612
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_015512.5(DNAH1):āc.11837T>Cā(p.Ile3946Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000093 in 1,613,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00012 ( 0 hom., cov: 33)
Exomes š: 0.000090 ( 0 hom. )
Consequence
DNAH1
NM_015512.5 missense
NM_015512.5 missense
Scores
2
10
5
Clinical Significance
Conservation
PhyloP100: 7.82
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH1 | NM_015512.5 | c.11837T>C | p.Ile3946Thr | missense_variant | 74/78 | ENST00000420323.7 | |
DNAH1 | XM_017006129.2 | c.11906T>C | p.Ile3969Thr | missense_variant | 76/80 | ||
DNAH1 | XM_017006130.2 | c.11837T>C | p.Ile3946Thr | missense_variant | 75/79 | ||
DNAH1 | XM_017006131.2 | c.11780T>C | p.Ile3927Thr | missense_variant | 75/79 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH1 | ENST00000420323.7 | c.11837T>C | p.Ile3946Thr | missense_variant | 74/78 | 1 | NM_015512.5 | P1 | |
DNAH1 | ENST00000486752.5 | n.12294T>C | non_coding_transcript_exon_variant | 73/77 | 2 | ||||
DNAH1 | ENST00000488988.5 | n.3623T>C | non_coding_transcript_exon_variant | 21/25 | 2 | ||||
DNAH1 | ENST00000490713.5 | c.2537T>C | p.Ile846Thr | missense_variant, NMD_transcript_variant | 17/20 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152200Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000643 AC: 16AN: 248890Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135056
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GnomAD4 exome AF: 0.0000903 AC: 132AN: 1461466Hom.: 0 Cov.: 32 AF XY: 0.0000812 AC XY: 59AN XY: 727032
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74352
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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 | Sep 07, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3946 of the DNAH1 protein (p.Ile3946Thr). This variant is present in population databases (rs374798612, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DNAH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 478404). 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: "Benign"; Align-GVGD: "Class C0"). 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 | Nov 30, 2022 | The c.11837T>C (p.I3946T) alteration is located in exon 74 (coding exon 73) of the DNAH1 gene. This alteration results from a T to C substitution at nucleotide position 11837, causing the isoleucine (I) at amino acid position 3946 to be replaced by a threonine (T). 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
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Vest4
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