rs137852626

Positions:

• chr19-17839585-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1333C>T (p.Arg445Ter) (NM_000215.4) variant in JAK3 is a nonsense variant observed to cause a premature stop codon in a gene in which loss-of-function is an established disease mechanism (PVS1).The filtering allele frequency in gnomAD v4.1.0 is 0.0000002800 (2/1179170 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting. Additionally, no homozygotes have been observed in gnomAD. (PM2_Supporting). At least one patient in the literature, LP1, presents JAk3 expression and phosphorylation absent; STAT5a phosphorylation is absent, and STAT6 phosphorylation is reduced. Thus: *Reduced or constitutive cytokine-induced tyrosine phosphorylation in patient cells (1pt) + *Reduced cytokine-induced phosphorylation of STAT5 in patient-derived T or B cells (1pt). Total 2 points, PP4_Moderate (PMID 9618765).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4_Moderate (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA120306/MONDO:0010938/121

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: JAK3 NM_000215.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 1.86

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 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.1333C>T	p.Arg445Ter	stop_gained	10/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.1333C>T	p.Arg445Ter	stop_gained	10/24		XP_047294742.1
JAK3	XM_011527991.3	c.1333C>T	p.Arg445Ter	stop_gained	10/14		XP_011526293.2
JAK3	XR_007066796.1	n.1383C>T		non_coding_transcript_exon_variant	10/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.1333C>T	p.Arg445Ter	stop_gained	10/24	5	NM_000215.4	ENSP00000391676	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459350 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725604

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jun 13, 2024	The c.1333C>T (p.Arg445Ter) (NM_000215.4) variant in JAK3 is a nonsense variant observed to cause a premature stop codon in a gene in which loss-of-function is an established disease mechanism (PVS1). The filtering allele frequency in gnomAD v4.1.0 is 0.0000002800 (2/1179170 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting. Additionally, no homozygotes have been observed in gnomAD. (PM2_Supporting). At least one patient in the literature, LP1, presents JAk3 expression and phosphorylation absent; STAT5a phosphorylation is absent, and STAT6 phosphorylation is reduced. Thus: *Reduced or constitutive cytokine-induced tyrosine phosphorylation in patient cells (1pt) + *Reduced cytokine-induced phosphorylation of STAT5 in patient-derived T or B cells (1pt). Total 2 points, PP4_Moderate (PMID 9618765). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4_Moderate (VCEP specifications version 1). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Arg445*) in the JAK3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAK3 are known to be pathogenic (PMID: 7481768, 11668621). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of severe combined immunodeficiency (PMID: 9354668). This variant is also known as 1428C>T. ClinVar contains an entry for this variant (Variation ID: 9364). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.083	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.96
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs137852626; hg19: chr19-17950394;