rs760063063
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_015512.5(DNAH1):c.10278+3C>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000816 in 1,593,814 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Consequence
DNAH1
NM_015512.5 splice_donor_region, intron
NM_015512.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001807
2
Clinical Significance
Conservation
PhyloP100: -1.92
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 Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
?
Variant 3-52392692-C-G is Benign according to our data. Variant chr3-52392692-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 544600.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH1 | NM_015512.5 | c.10278+3C>G | splice_donor_region_variant, intron_variant | ENST00000420323.7 | |||
DNAH1 | XM_017006129.2 | c.10347+3C>G | splice_donor_region_variant, intron_variant | ||||
DNAH1 | XM_017006130.2 | c.10278+3C>G | splice_donor_region_variant, intron_variant | ||||
DNAH1 | XM_017006131.2 | c.10221+3C>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH1 | ENST00000420323.7 | c.10278+3C>G | splice_donor_region_variant, intron_variant | 1 | NM_015512.5 | P1 | |||
DNAH1 | ENST00000490713.5 | c.978+3C>G | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 5 | |||||
DNAH1 | ENST00000486752.5 | n.10735+3C>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 2 | |||||
DNAH1 | ENST00000488988.5 | n.2064+3C>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 151974Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000382 AC: 8AN: 209230Hom.: 0 AF XY: 0.0000177 AC XY: 2AN XY: 113302
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GnomAD4 exome AF: 0.00000694 AC: 10AN: 1441840Hom.: 0 Cov.: 33 AF XY: 0.00000559 AC XY: 4AN XY: 715272
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2022 | This sequence change falls in intron 64 of the DNAH1 gene. It does not directly change the encoded amino acid sequence of the DNAH1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs760063063, gnomAD 0.03%). 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: 544600). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. - |
DNAH1-related condition Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 01, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at