4-3463437-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting
The NM_173660.5(DOK7):c.54+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000064 ( 0 hom., cov: 25)
Exomes 𝑓: 0.00020 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
DOK7
NM_173660.5 splice_region, intron
NM_173660.5 splice_region, intron
Scores
2
Splicing: ADA: 0.002728
2
Clinical Significance
Conservation
PhyloP100: -0.119
Genes affected
DOK7 (HGNC:26594): (docking protein 7) The protein encoded by this gene is essential for neuromuscular synaptogenesis. The protein functions in aneural activation of muscle-specific receptor kinase, which is required for postsynaptic differentiation, and in the subsequent clustering of the acetylcholine receptor in myotubes. This protein can also induce autophosphorylation of muscle-specific receptor kinase. Mutations in this gene are a cause of familial limb-girdle myasthenia autosomal recessive, which is also known as congenital myasthenic syndrome type 1B. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BS1
?
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000205 (94/459580) while in subpopulation EAS AF= 0.00794 (92/11588). AF 95% confidence interval is 0.00663. There are 0 homozygotes in gnomad4_exome. There are 41 alleles in male gnomad4_exome subpopulation. Median coverage is 6. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOK7 | NM_173660.5 | c.54+8C>T | splice_region_variant, intron_variant | ENST00000340083.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOK7 | ENST00000340083.6 | c.54+8C>T | splice_region_variant, intron_variant | 1 | NM_173660.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 6AN: 93336Hom.: 0 Cov.: 25 FAILED QC
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GnomAD3 exomes AF: 0.0000491 AC: 2AN: 40752Hom.: 0 AF XY: 0.0000418 AC XY: 1AN XY: 23896
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GnomAD4 exome AF: 0.000205 AC: 94AN: 459580Hom.: 0 Cov.: 6 AF XY: 0.000173 AC XY: 41AN XY: 236972
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000643 AC: 6AN: 93352Hom.: 0 Cov.: 25 AF XY: 0.0000677 AC XY: 3AN XY: 44318
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change falls in intron 1 of the DOK7 gene. It does not directly change the encoded amino acid sequence of the DOK7 protein. While this variant is present in population databases (rs577687998), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with DOK7-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at