rs886039394

Variant names:

• chr19-17837150-C-T
• rs886039394
• NM_000215.4:c.1765G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000215.4(JAK3):​c.1765G>A​(p.Gly589Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000355 in 1,407,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G589G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.20

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-17837150-C-T is Pathogenic according to our data. Variant chr19-17837150-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17837150-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.1765G>A	p.Gly589Ser	missense_variant	Exon 13 of 24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.1765G>A	p.Gly589Ser	missense_variant	Exon 13 of 24		XP_047294742.1
JAK3	XM_011527991.3	c.1765G>A	p.Gly589Ser	missense_variant	Exon 13 of 14		XP_011526293.2
JAK3	XR_007066796.1	n.1815G>A		non_coding_transcript_exon_variant	Exon 13 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.1765G>A	p.Gly589Ser	missense_variant	Exon 13 of 24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000355 AC: 5 AN: 1407352 Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2 AN XY: 695120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000272

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000369

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 25, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 589 of the JAK3 protein (p.Gly589Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 14615376, 33040328). ClinVar contains an entry for this variant (Variation ID: 265205). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt JAK3 protein function. Experimental studies have shown that this missense change affects JAK3 function (PMID: 14615376). For these reasons, this variant has been classified as Pathogenic. -

Severe combined immunodeficiency disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 20, 2024

Variant summary: JAK3 c.1765G>A (p.Gly589Ser) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1765G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Severe Combined Immunodeficiency (El Hawary_2021, El Hawary_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abrogation of JAK3 kinase activity (Roberts_2004). The following publications have been ascertained in the context of this evaluation (PMID: 33040328, 35482138, 14615376). ClinVar contains an entry for this variant (Variation ID: 265205). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2016

The G589S pathogenic variant in the JAK3 gene has been reported previously in the homozygous state in association with Severe Combined Immunodeficiency (SCID) (Roberts et al., 2004; Pasic et al., 2014). The G589S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G589S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This variant is located in the conserved JH2 domain of the JAK3 protein, and in vitro functional studies showed that this variant disrupts the normal catalytic functions of the protein (Roberts et al., 2004). -

Adenoid cystic carcinoma Other:1

-, no assertion criteria provided

research

Genome Sciences Centre, British Columbia Cancer Agency

Nov 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.5	M;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.85
MutPred		0.98		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.92
MPC		1.3
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs886039394; hg19: chr19-17947959;