Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_002227.4(JAK1):c.2199A>G(p.Pro733Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,613,788 control chromosomes in the GnomAD database, including 62,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
JAK1 (HGNC:6190): (Janus kinase 1) This gene encodes a membrane protein that is a member of a class of protein-tyrosine kinases (PTK) characterized by the presence of a second phosphotransferase-related domain immediately N-terminal to the PTK domain. The encoded kinase phosphorylates STAT proteins (signal transducers and activators of transcription) and plays a key role in interferon-alpha/beta, interferon-gamma, and cytokine signal transduction. This gene plays a crucial role in effecting the expression of genes that mediate inflammation, epithelial remodeling, and metastatic cancer progression. This gene is a key component of the interleukin-6 (IL-6)/JAK1/STAT3 immune and inflammation response and is a therapeutic target for alleviating cytokine storms. The kinase activity of this gene is directly inhibited by the suppressor of cytokine signalling 1 (SOCS1) protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2020]
JAK1 Gene-Disease associations (from GenCC):
autoinflammation, immune dysregulation, and eosinophilia
Our verdict: Benign. The variant received -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BP6
Variant 1-64844806-T-C is Benign according to our data. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-2.98 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is classified as Benign based on local population frequency. This variant was detected in 49% of patients studied by a panel of primary immunodeficiencies. Number of patients: 47. Only high quality variants are reported. -