Genetic Variant JAK3:p.Gly589Arg (chr19-17837150-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000215.4(JAK3):c.1765G>C(p.Gly589Arg) 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 Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.20

Publications

0 publications found

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]

JAK3 Gene-Disease associations (from GenCC):

T-B+ severe combined immunodeficiency due to JAK3 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Orphanet

JAK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

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 ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.1765G>C	p.Gly589Arg	missense	Exon 13 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.1765G>C	p.Gly589Arg	missense	Exon 13 of 24	NP_001427368.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
JAK3	ENST00000458235.7	TSL:5 MANE Select	c.1765G>C	p.Gly589Arg	missense	Exon 13 of 24	ENSP00000391676.1
JAK3	ENST00000527670.5	TSL:1	c.1765G>C	p.Gly589Arg	missense	Exon 12 of 23	ENSP00000432511.1
JAK3	ENST00000534444.1	TSL:1	c.1765G>C	p.Gly589Arg	missense	Exon 13 of 23	ENSP00000436421.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1407354

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

695122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32136

American (AMR)

AF:

0.00

AC:

AN:

37308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25252

East Asian (EAS)

AF:

0.00

AC:

AN:

36702

South Asian (SAS)

AF:

0.00

AC:

AN:

79706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4210

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1084288

Other (OTH)

AF:

0.00

AC:

AN:

58252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.9

PhyloP100

7.2

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.92

MutPred

0.96

Gain of MoRF binding (P = 0.0348)

MVP

0.95

MPC

1.5

ClinPred

1.0

GERP RS

4.2

Varity_R

0.89

gMVP

0.76

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over