4-3493358-GC-GCC
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_173660.5(DOK7):c.1378dup(p.Gln460ProfsTer59) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,596,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A458A) has been classified as Likely benign.
Frequency
Consequence
NM_173660.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOK7 | NM_173660.5 | c.1378dup | p.Gln460ProfsTer59 | frameshift_variant | 7/7 | ENST00000340083.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOK7 | ENST00000340083.6 | c.1378dup | p.Gln460ProfsTer59 | frameshift_variant | 7/7 | 1 | NM_173660.5 | P1 | |
DOK7 | ENST00000515886.5 | c.448dup | p.Gln150ProfsTer59 | frameshift_variant | 4/4 | 2 | |||
DOK7 | ENST00000643608.1 | c.946dup | p.Gln316ProfsTer220 | frameshift_variant | 5/8 | ||||
DOK7 | ENST00000507039.5 | c.*599dup | 3_prime_UTR_variant | 7/7 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152210Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000527 AC: 11AN: 208604Hom.: 0 AF XY: 0.0000607 AC XY: 7AN XY: 115332
GnomAD4 exome AF: 0.0000201 AC: 29AN: 1444706Hom.: 0 Cov.: 95 AF XY: 0.0000195 AC XY: 14AN XY: 717054
GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152210Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5AN XY: 74360
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 10 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 27, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2008 | - - |
Fetal akinesia deformation sequence 3 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 31, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | research | Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences | Dec 12, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 27, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | DOK7: PP1:Strong, PM2, PVS1:Moderate, PP4, PS3:Supporting - |
Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change results in a frameshift in the DOK7 gene (p.Gln460Profs*59). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the DOK7 protein and extend the protein by 13 additional amino acid residues. This variant is present in population databases (rs747302811, gnomAD 0.03%). This frameshift has been observed in individuals with congenital myasthenic syndrome (PMID: 16917026, 18626973). ClinVar contains an entry for this variant (Variation ID: 1282). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects DOK7 function (PMID: 18626973). This variant results in an extension of the DOK7 protein. Other variant(s) that result in a similarly extended protein product (p.Pro504Serfs*15) have been observed in individuals with DOK7-related disease (PMID: 16917026). This suggests that these extensions may be clinically significant. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at