dbSNP rs7250423: JAK3:c.-14+138G>A (chr19-17847808-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000215.4(JAK3):c.-14+138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 239,806 control chromosomes in the GnomAD database, including 7,794 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 7224 hom., cov: 33)

Exomes 𝑓: 0.085 ( 570 hom. )

Consequence

JAK3
NM_000215.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.40

Publications

7 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4 link	c.-14+138G>A	intron_variant	Intron 1 of 23	ENST00000458235.7	NP_000206.2	P52333-1A0A024R7M7
JAK3	NM_001440439.1 link	c.-45+138G>A	intron_variant	Intron 1 of 23		NP_001427368.1
JAK3	XM_011527991.3 link	c.-14+138G>A	intron_variant	Intron 1 of 13		XP_011526293.2
JAK3	XR_007066796.1 link	n.37+138G>A	intron_variant	Intron 1 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 link	c.-14+138G>A		intron_variant	Intron 1 of 23	5	NM_000215.4	ENSP00000391676.1		P52333-1

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33362

AN:

152146

Hom.:

7205

Cov.:

show subpopulations

Gnomad AFR

AF:

0.560

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.149

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.0325

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0738

Gnomad OTH

AF:

0.191

GnomAD4 exome

AF:

0.0853

AC:

7468

AN:

87546

Hom.:

570

AF XY:

0.0818

AC XY:

3370

AN XY:

41208

show subpopulations

African (AFR)

AF:

0.534

AC:

901

AN:

1688

American (AMR)

AF:

0.129

AC:

AN:

612

Ashkenazi Jewish (ASJ)

AF:

0.0884

AC:

176

AN:

1990

East Asian (EAS)

AF:

0.205

AC:

1164

AN:

5686

South Asian (SAS)

AF:

0.0699

AC:

AN:

1388

European-Finnish (FIN)

AF:

0.0435

AC:

AN:

Middle Eastern (MID)

AF:

0.0973

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.0632

AC:

4532

AN:

71728

Other (OTH)

AF:

0.119

AC:

488

AN:

4110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

298

596

893

1191

1489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.220

AC:

33434

AN:

152260

Hom.:

7224

Cov.:

AF XY:

0.217

AC XY:

16125

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.560

AC:

23239

AN:

41504

American (AMR)

AF:

0.149

AC:

2276

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

358

AN:

3468

East Asian (EAS)

AF:

0.223

AC:

1152

AN:

5176

South Asian (SAS)

AF:

0.117

AC:

563

AN:

4830

European-Finnish (FIN)

AF:

0.0325

AC:

345

AN:

10624

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0737

AC:

5017

AN:

68036

Other (OTH)

AF:

0.194

AC:

411

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

995

1991

2986

3982

4977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.124

Hom.:

2816

Bravo

AF:

0.243

Asia WGS

AF:

0.205

AC:

712

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.43

(source)

DANN

Benign

0.79

PhyloP100

-3.4

PromoterAI

0.015

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Computational scores

Splicing

Publications

Other links and lift over