19-17837171-G-A

Variant names:

• chr19-17837171-G-A
• rs193922361
• NM_000215.4:c.1744C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4_Moderate PM3 PM2_Supporting PM4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000215.4(JAK3):c.1744C>T variant is predicted to cause the Arg582Trp missense substitution, however it has been observed in patient cDNA to cause an in-frame deletion of 213bp (71 amino acids; p.Ser568_Leu638del) due to skipping of exon 13 and 14 (PMID:9753072). The deleted region contains the NM_000215.4(JAK3):c.1796T>G (p.Val599Gly) variant which has been classified by the SCID VCEP as VUS (PM4_supporting). This variant was identified in at least one T-B+ SCID patient in whom, IL-2-induced JAK3 phosphorylation showed that the JAK3 protein was only marginally activated, and IL-2-induced phosphorylation of STAT5B/A was not detected in BCLs from the patient. This combination is highly specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (PMID:9753072; PP4_moderate). This patient (PMID:9753072) was homozygous for the variant and two additional patients are compound heterozygous with second variants confirmed in trans (but not yet classified by the SCID-VCEP so considered VUS), Leu1017Pro (PMID:33777394) and c.115dup (PMID:21184155) for three patients in total with this variant (PM3). The highest population allele frequency in gnomAD v2.1.1 is 0.00001239 (1/80718 alleles in the European non-Finnish population), which is lower than the ClinGen SCID VCEP threshold of <0.000115 (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting, PM3, PM4_supporting, PP4_moderate. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214079/MONDO:0010938/121

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 3.53
• Publications: 10 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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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.1744C>T	p.Arg582Trp	missense	Exon 13 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.1744C>T	p.Arg582Trp	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.1744C>T	p.Arg582Trp	missense	Exon 13 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000527670.5	TSL:1	c.1744C>T	p.Arg582Trp	missense	Exon 12 of 23	ENSP00000432511.1	P52333-1
	JAK3	ENST00000534444.1	TSL:1	c.1744C>T	p.Arg582Trp	missense	Exon 13 of 23	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000105 AC: 2 AN: 190146 AF XY: 0.00000987

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.000199

GnomAD4 exome AF: 0.00000423 AC: 6 AN: 1419640 Hom.: 0 Cov.: 32 AF XY: 0.00000285 AC XY: 2 AN XY: 702196

African (AFR) AF: 0.00 AC: 0 AN: 32562

American (AMR) AF: 0.00 AC: 0 AN: 39048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25370

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37578

South Asian (SAS) AF: 0.00 AC: 0 AN: 80640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50516

Middle Eastern (MID) AF: 0.000437 AC: 2 AN: 4580

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1090568

Other (OTH) AF: 0.00 AC: 0 AN: 58778

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74288

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00000901 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	T-B+ severe combined immunodeficiency due to JAK3 deficiency (3)
1	-	-	Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.5
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.85		Loss of solvent accessibility (P = 0.0299)
MVP		0.68
MPC		1.1
ClinPred		0.93	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.38
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.13		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: rs193922361; hg19: chr19-17947980; COSMIC: COSV105940653;