NM_000215.4:c.2164G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_SupportingBA1

This summary comes from the ClinGen Evidence Repository: NM_000215.4(JAK3):c.2164G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 722 (p.Val722Ile).The filtering allele frequency (the lower threshold of the 95% CI of 12957/1180016) of the c.2164G>A variant in JAK3 is 0.01082 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1). Additionally, 120 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and B2_Supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA160225/MONDO:0010938/121

Frequency

Genomes: 𝑓 0.0075 ( 12 hom., cov: 32)

Exomes 𝑓: 0.010 ( 108 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:10O:2

Conservation

PhyloP100: 3.04

Publications

137 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

JAK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BS2

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

BA1

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.2164G>A	p.Val722Ile	missense	Exon 16 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.2164G>A	p.Val722Ile	missense	Exon 16 of 24	NP_001427368.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JAK3	ENST00000458235.7	TSL:5 MANE Select	c.2164G>A	p.Val722Ile	missense	Exon 16 of 24	ENSP00000391676.1	P52333-1
JAK3	ENST00000527670.5	TSL:1	c.2164G>A	p.Val722Ile	missense	Exon 15 of 23	ENSP00000432511.1	P52333-1
JAK3	ENST00000534444.1	TSL:1	c.2164G>A	p.Val722Ile	missense	Exon 16 of 23	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes

AF:

0.00750

AC:

1141

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00695

Gnomad ASJ

AF:

0.0262

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00862

AC:

2168

AN:

251398

AF XY:

0.00902

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00509

Gnomad ASJ exome

AF:

0.0255

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00360

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.00880

GnomAD4 exome

AF:

0.00999

AC:

14604

AN:

1461886

Hom.:

108

Cov.:

AF XY:

0.0101

AC XY:

7348

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00260

AC:

AN:

33480

American (AMR)

AF:

0.00568

AC:

254

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0260

AC:

679

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00526

AC:

454

AN:

86258

European-Finnish (FIN)

AF:

0.00468

AC:

250

AN:

53418

Middle Eastern (MID)

AF:

0.0229

AC:

132

AN:

5768

European-Non Finnish (NFE)

AF:

0.0109

AC:

12172

AN:

1112006

Other (OTH)

AF:

0.00952

AC:

575

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

943

1885

2828

3770

4713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.00748

AC:

1139

AN:

152254

Hom.:

Cov.:

AF XY:

0.00676

AC XY:

503

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

41556

American (AMR)

AF:

0.00694

AC:

106

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00643

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00330

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0115

AC:

785

AN:

68010

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

116

173

231

289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0107

Hom.:

Bravo

AF:

0.00761

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0133

AC:

114

ExAC

AF:

0.00863

AC:

1048

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0155

EpiControl

AF:

0.0171

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

T-B+ severe combined immunodeficiency due to JAK3 deficiency (5)

not provided (5)

JAK3-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.41

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

PhyloP100

3.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.80

REVEL

Benign

0.16

Sift

Uncertain

0.029

Sift4G

Benign

0.067

Polyphen

0.0010

Vest4

0.032

MVP

0.35

MPC

0.39

ClinPred

0.016

GERP RS

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.048

gMVP

0.53

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over