rs193922361

Positions:

chr19-17837171-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM4_SupportingPP4_ModeratePM2_SupportingPM3

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

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 3.53

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
JAK3	NM_000215.4 linkuse as main transcript	c.1744C>T	p.Arg582Trp	missense_variant	13/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1 linkuse as main transcript	c.1744C>T	p.Arg582Trp	missense_variant	13/24		XP_047294742.1
JAK3	XM_011527991.3 linkuse as main transcript	c.1744C>T	p.Arg582Trp	missense_variant	13/14		XP_011526293.2
JAK3	XR_007066796.1 linkuse as main transcript	n.1794C>T		non_coding_transcript_exon_variant	13/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 linkuse as main transcript	c.1744C>T	p.Arg582Trp	missense_variant	13/24	5	NM_000215.4	ENSP00000391676	P1	P52333-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

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

GnomAD4 exome

AF:

0.00000423

AC:

AN:

1419640

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

702196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000266

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000275

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 582 of the JAK3 protein (p.Arg582Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 9753072, 21184155, 30697212, 33365035). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as substitution of Arg to Trp at codon 577. ClinVar contains an entry for this variant (Variation ID: 36415). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt JAK3 protein function. Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 9753072). For these reasons, this variant has been classified as Pathogenic. -

Severe combined immunodeficiency disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;D;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;.;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.3

M;M;M

MutationTaster

Benign

0.69

N;N;N

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.010

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.66

MutPred

0.85

Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);

MVP

0.68

MPC

1.1

ClinPred

0.93

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over