rs137852626

Variant names:

• chr19-17839585-G-A
• rs137852626
• NM_000215.4:c.1333C>T

Variant summary

Our verdict is Pathogenic. The variant received 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:4
• Conservation: PhyloP100: 1.86
• Publications: 6 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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.1333C>T	p.Arg445*	stop_gained	Exon 10 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.1333C>T	p.Arg445*	stop_gained	Exon 10 of 24		NP_001427368.1
JAK3	XM_011527991.3	c.1333C>T	p.Arg445*	stop_gained	Exon 10 of 14		XP_011526293.2
JAK3	XR_007066796.1	n.1383C>T		non_coding_transcript_exon_variant	Exon 10 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.1333C>T	p.Arg445*	stop_gained	Exon 10 of 24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 243658 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 85444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111156

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency Pathogenic:4

Jun 13, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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).

May 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.0	.;.;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.061
LIST_S2	Benign	0.0	.;.;.
MetaRNN	Benign	0.0	.;.;.
MutationAssessor	Benign	0.0	.;.;.
PhyloP100		1.9
PROVEAN	Benign	0.0	.;.;.
Sift	Pathogenic	0.0	.;.;.
Sift4G	Pathogenic	0.0	.;.;.
Vest4		0.96
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852626; hg19: chr19-17950394;