chr19-17837150-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000321792: "In vitro functional studies showed that this variant disrupts the normal catalytic functions of the protein." PMID:24076290" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G589G) has been classified as Likely pathogenic. The gene JAK3 is included in the ClinGen Criteria Specification Registry.

• 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
• Publications: 7 publications found

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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Specifications for JAK3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000321792: "In vitro functional studies showed that this variant disrupts the normal catalytic functions of the protein." PMID:24076290; SCV004297955: Experimental studies have shown that this missense change affects JAK3 function (PMID: 14615376).; SCV005395272: The most pronounced variant effect results in abrogation of JAK3 kinase activity (Roberts_2004).
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 265205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.1765G>A	p.Gly589Ser	missense	Exon 13 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.1765G>A	p.Gly589Ser	missense	Exon 13 of 24	NP_001427368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.1765G>A	p.Gly589Ser	missense	Exon 13 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000527670.5	TSL:1	c.1765G>A	p.Gly589Ser	missense	Exon 12 of 23	ENSP00000432511.1	P52333-1
	JAK3	ENST00000534444.1	TSL:1	c.1765G>A	p.Gly589Ser	missense	Exon 13 of 23	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000577 AC: 1 AN: 173398 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000378

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 32136

American (AMR) AF: 0.00 AC: 0 AN: 37308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25252

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36702

South Asian (SAS) AF: 0.00 AC: 0 AN: 79706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4210

European-Non Finnish (NFE) AF: 0.00000369 AC: 4 AN: 1084286

Other (OTH) AF: 0.00 AC: 0 AN: 58252

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Severe combined immunodeficiency disease (1)
1	-	-	T-B+ severe combined immunodeficiency due to JAK3 deficiency (1)
-	-	-	Adenoid cystic carcinoma (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.98		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
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs886039394; hg19: chr19-17947959; COSMIC: COSV108261898; COSMIC: COSV108261898;