19-17843141-G-C

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: The NM_000215.4(JAK3):c.452C>G (p.Pro151Arg) variant in JAK3 is a missense variant predicted to cause the substitution of Proline by Arginine at amino acid 151 (p.Pro151Arg). The Popmax Filtering allele frequency (95% CI) of the variant is 0.008679 in gnomAD v.4 for European (non-Finnish) population 10486/1179548 alleles, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, therefore, meets this criterion (BA1). Also, 59 homozygous adults are reported on GnomAD v2.1.1 (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign 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. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA160252/MONDO:0010938/121

Frequency

Genomes: 𝑓 0.0064 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 52 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:7O:1

Conservation

PhyloP100: -0.433

Publications

25 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 -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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.452C>G	p.Pro151Arg	missense	Exon 5 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.452C>G	p.Pro151Arg	missense	Exon 5 of 24	NP_001427368.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
JAK3	ENST00000458235.7	TSL:5 MANE Select	c.452C>G	p.Pro151Arg	missense	Exon 5 of 24	ENSP00000391676.1
JAK3	ENST00000527670.5	TSL:1	c.452C>G	p.Pro151Arg	missense	Exon 4 of 23	ENSP00000432511.1
JAK3	ENST00000534444.1	TSL:1	c.452C>G	p.Pro151Arg	missense	Exon 5 of 23	ENSP00000436421.1

Frequencies

GnomAD3 genomes

AF:

0.00642

AC:

977

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00289

Gnomad FIN

AF:

0.0107

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.00994

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00592

AC:

1400

AN:

236668

AF XY:

0.00626

show subpopulations

Gnomad AFR exome

AF:

0.000891

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0114

Gnomad NFE exome

AF:

0.00820

Gnomad OTH exome

AF:

0.00719

GnomAD4 exome

AF:

0.00791

AC:

11511

AN:

1455712

Hom.:

Cov.:

AF XY:

0.00782

AC XY:

5668

AN XY:

724368

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

33440

American (AMR)

AF:

0.00231

AC:

103

AN:

44578

Ashkenazi Jewish (ASJ)

AF:

0.00859

AC:

224

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.00375

AC:

323

AN:

86114

European-Finnish (FIN)

AF:

0.00966

AC:

467

AN:

48326

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00883

AC:

9810

AN:

1111546

Other (OTH)

AF:

0.00767

AC:

462

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

723

1446

2168

2891

3614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.00642

AC:

978

AN:

152292

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

506

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

41552

American (AMR)

AF:

0.00261

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00290

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0107

AC:

114

AN:

10622

Middle Eastern (MID)

AF:

0.0240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00994

AC:

676

AN:

68002

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

106

158

211

264

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:

0.00840

Hom.:

Bravo

AF:

0.00552

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00722

AC:

ExAC

AF:

0.00549

AC:

663

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0119

EpiControl

AF:

0.00838

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

T-B+ severe combined immunodeficiency due to JAK3 deficiency (3)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

6.3

(source)

DANN

Benign

0.87

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.6

PhyloP100

-0.43

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.45

Sift

Benign

0.074

Sift4G

Benign

0.13

Polyphen

0.0010

Vest4

0.20

MVP

0.98

MPC

0.51

ClinPred

0.013

GERP RS

-4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.78

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over