rs3212723

Positions:

chr19-17843406-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2_SupportingBA1

This summary comes from the ClinGen Evidence Repository: The c.394C>A (NM_000215.4) variant in JAK3 is a missense variant predicted to cause substitution of Proline by Threonine at amino acid 132 (p.Pro132Thr).The filtering allele frequency (the lower threshold of the 95% CI of 6500/74518) of the c.394C>A variant in JAK3 is 0.08599 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1).Furthermore, 321 adult homozygous were described in GnomAD v.2.1.1, meeting BS2_Supporting criteria.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/CA160246/MONDO:0010938/121

Frequency

Genomes: 𝑓 0.025 ( 169 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 152 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7O:1

Conservation

PhyloP100: 1.91

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 links:

JAK3 (HGNC:):

JAK3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4 linkuse as main transcript	c.394C>A	p.Pro132Thr	missense_variant	4/24	ENST00000458235.7	NP_000206.2	P52333-1A0A024R7M7
JAK3	XM_047438786.1 linkuse as main transcript	c.394C>A	p.Pro132Thr	missense_variant	4/24		XP_047294742.1
JAK3	XM_011527991.3 linkuse as main transcript	c.394C>A	p.Pro132Thr	missense_variant	4/14		XP_011526293.2
JAK3	XR_007066796.1 linkuse as main transcript	n.444C>A		non_coding_transcript_exon_variant	4/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 linkuse as main transcript	c.394C>A	p.Pro132Thr	missense_variant	4/24	5	NM_000215.4	ENSP00000391676.1		P52333-1

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3736

AN:

152174

Hom.:

169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0861

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00617

AC:

1363

AN:

220906

Hom.:

AF XY:

0.00409

AC XY:

492

AN XY:

120248

show subpopulations

Gnomad AFR exome

AF:

0.0919

Gnomad AMR exome

AF:

0.00415

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000287

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000718

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00244

AC:

3526

AN:

1443296

Hom.:

152

Cov.:

AF XY:

0.00207

AC XY:

1487

AN XY:

716650

show subpopulations

Gnomad4 AFR exome

AF:

0.0887

Gnomad4 AMR exome

AF:

0.00476

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000238

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000489

Gnomad4 OTH exome

AF:

0.00527

GnomAD4 genome

AF:

0.0246

AC:

3747

AN:

152292

Hom.:

169

Cov.:

AF XY:

0.0233

AC XY:

1734

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0861

Gnomad4 AMR

AF:

0.00875

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00749

Hom.:

Bravo

AF:

0.0283

ESP6500AA

AF:

0.0877

AC:

386

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00701

AC:

845

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Benign:4

Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 23, 2024	The c.394C>A (NM_000215.4) variant in JAK3 is a missense variant predicted to cause substitution of Proline by Threonine at amino acid 132 (p.Pro132Thr). The filtering allele frequency (the lower threshold of the 95% CI of 6500/74518) of the c.394C>A variant in JAK3 is 0.08599 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1). Furthermore, 321 adult homozygous were described in GnomAD v.2.1.1, meeting BS2_Supporting criteria. 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). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 29, 2021	- -

not specified

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

JAK3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.19

T;T;.

Eigen

Benign

0.090

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.60

T;.;T

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.7

L;L;L

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.83

N;N;N

REVEL

Benign

0.092

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.22

B;B;B

Vest4

0.42

MVP

0.73

MPC

1.1

ClinPred

0.025

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over