rs886039394

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000215.4(JAK3):​c.1765G>T​(p.Gly589Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000711 in 1,407,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G589S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

15
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.20
Variant links:
Genes affected
JAK3 (HGNC:6193): (Janus kinase 3) The protein encoded by this gene is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations in this gene are associated with autosomal SCID (severe combined immunodeficiency disease). [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a domain Protein kinase 1 (size 260) in uniprot entity JAK3_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_000215.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-17837150-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
JAK3NM_000215.4 linkc.1765G>T p.Gly589Cys missense_variant Exon 13 of 24 ENST00000458235.7 NP_000206.2 P52333-1A0A024R7M7
JAK3XM_047438786.1 linkc.1765G>T p.Gly589Cys missense_variant Exon 13 of 24 XP_047294742.1
JAK3XM_011527991.3 linkc.1765G>T p.Gly589Cys missense_variant Exon 13 of 14 XP_011526293.2
JAK3XR_007066796.1 linkn.1815G>T non_coding_transcript_exon_variant Exon 13 of 20

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
JAK3ENST00000458235.7 linkc.1765G>T p.Gly589Cys missense_variant Exon 13 of 24 5 NM_000215.4 ENSP00000391676.1 P52333-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.11e-7
AC:
1
AN:
1407354
Hom.:
0
Cov.:
32
AF XY:
0.00000144
AC XY:
1
AN XY:
695122
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.22e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D;D;.
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;.;D
M_CAP
Pathogenic
0.62
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
3.2
M;M;M
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-8.3
D;D;D
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.90
MutPred
0.96
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.95
MPC
1.4
ClinPred
1.0
D
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.92
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-17947959; API