dbSNP rs35458530: JAK3:p.Ala753Ala (chr19-17834662-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000215.4(JAK3):c.2259C>T(p.Ala753Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,058 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A753A) has been classified as Likely benign. The gene JAK3 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.010 ( 12 hom., cov: 32)

Exomes 𝑓: 0.013 ( 148 hom. )

Consequence

JAK3
NM_000215.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.180

Publications

8 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

Specifications for JAK3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 19-17834662-G-A is Benign according to our data. Variant chr19-17834662-G-A is described in ClinVar as Benign. ClinVar VariationId is 36418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.18 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.01 (1525/152176) while in subpopulation NFE AF = 0.0147 (1001/67990). AF 95% confidence interval is 0.014. There are 12 homozygotes in GnomAd4. There are 717 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

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.2259C>T	p.Ala753Ala	synonymous	Exon 17 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.2259C>T	p.Ala753Ala	synonymous	Exon 17 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.2259C>T	p.Ala753Ala	synonymous	Exon 17 of 24	ENSP00000391676.1	P52333-1
JAK3	ENST00000527670.5	TSL:1	c.2259C>T	p.Ala753Ala	synonymous	Exon 16 of 23	ENSP00000432511.1	P52333-1
JAK3	ENST00000534444.1	TSL:1	c.2259C>T	p.Ala753Ala	synonymous	Exon 17 of 23	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1524

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.0157

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0147

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0104

AC:

2620

AN:

251314

AF XY:

0.0105

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.00440

Gnomad ASJ exome

AF:

0.00983

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.0161

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.0128

AC:

18720

AN:

1461882

Hom.:

148

Cov.:

AF XY:

0.0125

AC XY:

9056

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00170

AC:

AN:

33480

American (AMR)

AF:

0.00494

AC:

221

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00983

AC:

257

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00313

AC:

270

AN:

86258

European-Finnish (FIN)

AF:

0.0165

AC:

883

AN:

53412

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0147

AC:

16334

AN:

1112008

Other (OTH)

AF:

0.0114

AC:

686

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1109

2217

3326

4434

5543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

610

1220

1830

2440

3050

<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:

0.0100

AC:

1525

AN:

152176

Hom.:

Cov.:

AF XY:

0.00963

AC XY:

717

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00248

AC:

103

AN:

41520

American (AMR)

AF:

0.0120

AC:

183

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00951

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00332

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0157

AC:

167

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0147

AC:

1001

AN:

67990

Other (OTH)

AF:

0.0104

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

147

220

294

367

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:

0.0102

Hom.:

Bravo

AF:

0.00957

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0126

EpiControl

AF:

0.0119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

T-B+ severe combined immunodeficiency due to JAK3 deficiency (2)

not specified (1)

Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.6

(source)

DANN

Benign

0.82

PhyloP100

-0.18

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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