rs193922362

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000215.4(JAK3):c.1767C>T(p.Gly589Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,405,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

JAK3
NM_000215.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: -0.269

Publications

4 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: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 19-17837148-G-A is Pathogenic according to our data. Variant chr19-17837148-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36416.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
JAK3	NM_000215.4 link	c.1767C>T	p.Gly589Gly	synonymous_variant	Exon 13 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1 link	c.1767C>T	p.Gly589Gly	synonymous_variant	Exon 13 of 24		NP_001427368.1
JAK3	XM_011527991.3 link	c.1767C>T	p.Gly589Gly	synonymous_variant	Exon 13 of 14		XP_011526293.2
JAK3	XR_007066796.1 link	n.1817C>T		non_coding_transcript_exon_variant	Exon 13 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 link	c.1767C>T	p.Gly589Gly	synonymous_variant	Exon 13 of 24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152074

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000583

AC:

AN:

171516

AF XY:

0.0000110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000143

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1405938

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

694338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32080

American (AMR)

AF:

0.00

AC:

AN:

37150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25246

East Asian (EAS)

AF:

0.00

AC:

AN:

36604

South Asian (SAS)

AF:

0.00

AC:

AN:

79640

European-Finnish (FIN)

AF:

0.0000810

AC:

AN:

49372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4176

European-Non Finnish (NFE)

AF:

0.0000138

AC:

AN:

1083484

Other (OTH)

AF:

0.000155

AC:

AN:

58186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74270

African (AFR)

AF:

0.00

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2080

Alfa

AF:

0.0000140

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Pathogenic:1Uncertain:1

Nov 23, 2020

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 589 of the JAK3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the JAK3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 7 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs193922362, ExAC 0.01%). This variant has been observed in individual(s) with severe combined immunodeficiency (PMID: 9354668, 23384681, 32754152). This variant is also known as a C to T transition at nt 1862. ClinVar contains an entry for this variant (Variation ID: 36416). Studies have shown that this variant results in the activation of a cryptic splice site in exon 13 (PMID: 9354668). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Severe combined immunodeficiency disease

Pathogenic:1

Aug 18, 2011

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

not provided

Pathogenic:1

Aug 23, 2016

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1767 C>T variant has been published previously in association with SCID (Candotti et al., 1997; Cattaneo et al., 2013). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. While this variant leads to a synonymous amino acid change, several in-silico splice prediction models predict that c.1767 C>T creates a cryptic donor site which may supplant the natural donor site of intron 13 and lead to abnormal gene splicing. Additionally, functional studies have shown that the variant causes the loss of 21 nucleotides upstream of the natural splice donor site, leading to impaired function of the JAK3 protein (Candotti et al., 1997). Therefore, we consider this variant to be pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

-0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.85

Position offset: 2

DS_DL_spliceai

0.45

Position offset: -19

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over