ClinVar

Description

The JAK3 p.Ala1090Thr variant was not identified in the literature but was identified in dbSNP (ID: rs144968714), ClinVar (classified as likely benign by Invitae) and LOVD 3.0 (variant effect not shared). The variant was identified in control databases in 127 of 280068 chromosomes at a frequency of 0.0004535 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 105 of 24964 chromosomes (freq: 0.004206), Other in 6 of 7206 chromosomes (freq: 0.000833), Latino in 6 of 35430 chromosomes (freq: 0.000169) and East Asian in 3 of 19948 chromosomes (freq: 0.00015), European (non-Finnish) in 7 of 126746 chromosomes (freq: 0.000055), but was not observed in the Ashkenazi Jewish, European (Finnish), or South Asian populations. The p.Ala1090 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.