rs200075643

Positions:

chr19-17835995-G-A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: NM_000215.4(JAK3):c.1843C>T (p.Arg615Cys) is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 615.The filtering allele frequency (the upper threshold of the 95% CI of 534/91086) of the c.1843C>T variant in JAK3 is 0.005451 for South Asian chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1 and therefore meets this criterion (BA1). Additionally, 5 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting).In summary, this variant meets the criteria to be classified as a Benign variant for autosomal recessive severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA160213/MONDO:0010938/121

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 5 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:4O:1

Conservation

PhyloP100: 1.79

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.1843C>T	p.Arg615Cys	missense_variant	14/24	ENST00000458235.7	NP_000206.2	P52333-1A0A024R7M7
JAK3	XM_047438786.1 linkuse as main transcript	c.1843C>T	p.Arg615Cys	missense_variant	14/24		XP_047294742.1
JAK3	XR_007066796.1 linkuse as main transcript	n.1893C>T		non_coding_transcript_exon_variant	14/20
JAK3	XM_011527991.3 linkuse as main transcript	c.*922C>T		downstream_gene_variant			XP_011526293.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 linkuse as main transcript	c.1843C>T	p.Arg615Cys	missense_variant	14/24	5	NM_000215.4	ENSP00000391676.1		P52333-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000784

AC:

197

AN:

251304

Hom.:

AF XY:

0.00102

AC XY:

139

AN XY:

135850

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 SAS exome

AF:

0.00627

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000371

AC:

542

AN:

1461804

Hom.:

Cov.:

AF XY:

0.000514

AC XY:

374

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00587

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000204

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000663

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000873

AC:

106

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Benign:3

Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Apr 03, 2024	NM_000215.4(JAK3):c.1843C>T (p.Arg615Cys) is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 615. The filtering allele frequency (the upper threshold of the 95% CI of 534/91086) of the c.1843C>T variant in JAK3 is 0.005451 for South Asian chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1 and therefore meets this criterion (BA1). Additionally, 5 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting). In summary, this variant meets the criteria to be classified as a Benign variant for autosomal recessive severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting (VCEP specifications version 1). -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

JAK3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2023

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

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.75

D;D;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.75

T;.;T

MetaRNN

Benign

0.0087

T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.96

L;L;L

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.19

MutPred

0.63

Loss of MoRF binding (P = 0.0214);Loss of MoRF binding (P = 0.0214);Loss of MoRF binding (P = 0.0214);

MVP

0.63

MPC

0.66

ClinPred

0.028

GERP RS

2.3

Varity_R

0.076

gMVP

0.56

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