rs2230589

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7BS2_SupportingBA1

This summary comes from the ClinGen Evidence Repository: The NM_000215.4(JAK3):c.2625C>T (p.Leu875=) synonymous variant occurs at a high allele frequency with a filtering allele frequency based on the European non-Finnish population (upper bound of 95% CI of 1934/129188 observed alleles) is 0.01456 in gnomAD v2.1.1 which is above the SCID-VCEP threshold (>0.00447; BA1). 17 adult homozygous individuals were reported in gnomAD, BS2_Supporting (European non-Finnish n=10, South Asian n=3, European Finnish n=2, and Other n=2).The variant has been reported in one patient in the literature (Patient 17 in PMID:19203666). Patient 17 has T-B+NK- (0 CD3 T cells, 0.14x10^9 B cells/L, 0.01x10^9 NK cells/L) SCID (0.5pt) and absent IL-2–induced STAT5 phosphorylation (1pt). This combination is specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (Total 1.5pt; PP4 not considered due to high allele frequency). A confirmed deleterious γc or JAK3 variant was not identified in Patient 17, although a number of sequence variants were identified in his JAK3 gene (IVS13-30c>t/wt, c.2625C>T (L875L)/wt, IVS 20+32T>C/wt). An affected sibling of Patient 17 also carried these same variants, whereas an unaffected sibling did not (PP1 not considered due to high allele frequency). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1, BS2_Supporting, and BP7. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214091/MONDO:0010938/121

Frequency

Genomes: 𝑓 0.0096 ( 11 hom., cov: 32)

Exomes 𝑓: 0.015 ( 193 hom. )

Consequence

JAK3
NM_000215.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: -0.0320

Publications

5 publications found

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 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

JAK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

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 link	c.2625C>T	p.Leu875Leu	synonymous_variant	Exon 19 of 24	ENST00000458235.7	NP_000206.2	P52333-1A0A024R7M7
JAK3	NM_001440439.1 link	c.2625C>T	p.Leu875Leu	synonymous_variant	Exon 19 of 24		NP_001427368.1
JAK3	XR_007066796.1 link	n.2675C>T		non_coding_transcript_exon_variant	Exon 19 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 link	c.2625C>T	p.Leu875Leu	synonymous_variant	Exon 19 of 24	5	NM_000215.4	ENSP00000391676.1		P52333-1

Frequencies

GnomAD3 genomes

AF:

0.00963

AC:

1466

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00582

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.00997

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0153

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.0107

AC:

2700

AN:

251480

AF XY:

0.0116

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.00382

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0121

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.0117

GnomAD4 exome

AF:

0.0146

AC:

21407

AN:

1461872

Hom.:

193

Cov.:

AF XY:

0.0146

AC XY:

10598

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00263

AC:

AN:

33480

American (AMR)

AF:

0.00409

AC:

183

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

113

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0143

AC:

1236

AN:

86258

European-Finnish (FIN)

AF:

0.0116

AC:

618

AN:

53420

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0165

AC:

18378

AN:

1111990

Other (OTH)

AF:

0.0118

AC:

711

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1336

2672

4008

5344

6680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

694

1388

2082

2776

3470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00960

AC:

1463

AN:

152340

Hom.:

Cov.:

AF XY:

0.00925

AC XY:

689

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00325

AC:

135

AN:

41584

American (AMR)

AF:

0.00582

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.0124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00997

AC:

106

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0153

AC:

1042

AN:

68028

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0123

Hom.:

Bravo

AF:

0.00884

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0161

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Nov 14, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000215.4(JAK3):c.2625C>T (p.Leu875=) synonymous variant occurs at a high allele frequency with a filtering allele frequency based on the European non-Finnish population (upper bound of 95% CI of 1934/129188 observed alleles) is 0.01456 in gnomAD v2.1.1 which is above the SCID-VCEP threshold (>0.00447; BA1). 17 adult homozygous individuals were reported in gnomAD, BS2_Supporting (European non-Finnish n=10, South Asian n=3, European Finnish n=2, and Other n=2). The variant has been reported in one patient in the literature (Patient 17 in PMID: 19203666). Patient 17 has T-B+NK- (0 CD3 T cells, 0.14x10^9 B cells/L, 0.01x10^9 NK cells/L) SCID (0.5pt) and absent IL-2–induced STAT5 phosphorylation (1pt). This combination is specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (Total 1.5pt; PP4 not considered due to high allele frequency). A confirmed deleterious γc or JAK3 variant was not identified in Patient 17, although a number of sequence variants were identified in his JAK3 gene (IVS13-30c>t/wt, c.2625C>T (L875L)/wt, IVS 20+32T>C/wt). An affected sibling of Patient 17 also carried these same variants, whereas an unaffected sibling did not (PP1 not considered due to high allele frequency). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1, BS2_Supporting, and BP7. (VCEP specifications version 1). -

not specified

Benign:1

Jan 31, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Severe combined immunodeficiency disease

Benign:1

Oct 29, 2011

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.3

(source)

DANN

Benign

0.62

PhyloP100

-0.032

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over