19-17834887-C-T

Position:

chr19-17834887-C-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: NM_000215.4(JAK3):c.2164G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 722 (p.Val722Ile).The filtering allele frequency (the lower threshold of the 95% CI of 12957/1180016) of the c.2164G>A variant in JAK3 is 0.01082 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1). Additionally, 120 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign 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 B2_Supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA160225/MONDO:0010938/121

Frequency

Genomes: 𝑓 0.0075 ( 12 hom., cov: 32)

Exomes 𝑓: 0.010 ( 108 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:10O:2

Conservation

PhyloP100: 3.04

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.2164G>A	p.Val722Ile	missense_variant	16/24	ENST00000458235.7	NP_000206.2	P52333-1A0A024R7M7
JAK3	XM_047438786.1 linkuse as main transcript	c.2164G>A	p.Val722Ile	missense_variant	16/24		XP_047294742.1
JAK3	XR_007066796.1 linkuse as main transcript	n.2214G>A		non_coding_transcript_exon_variant	16/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 linkuse as main transcript	c.2164G>A	p.Val722Ile	missense_variant	16/24	5	NM_000215.4	ENSP00000391676.1		P52333-1

Frequencies

GnomAD3 genomes

AF:

0.00750

AC:

1141

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00695

Gnomad ASJ

AF:

0.0262

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00862

AC:

2168

AN:

251398

Hom.:

AF XY:

0.00902

AC XY:

1226

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00509

Gnomad ASJ exome

AF:

0.0255

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00467

Gnomad FIN exome

AF:

0.00360

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.00880

GnomAD4 exome

AF:

0.00999

AC:

14604

AN:

1461886

Hom.:

108

Cov.:

AF XY:

0.0101

AC XY:

7348

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00260

Gnomad4 AMR exome

AF:

0.00568

Gnomad4 ASJ exome

AF:

0.0260

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00526

Gnomad4 FIN exome

AF:

0.00468

Gnomad4 NFE exome

AF:

0.0109

Gnomad4 OTH exome

AF:

0.00952

GnomAD4 genome

AF:

0.00748

AC:

1139

AN:

152254

Hom.:

Cov.:

AF XY:

0.00676

AC XY:

503

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.00694

Gnomad4 ASJ

AF:

0.0262

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00643

Gnomad4 FIN

AF:

0.00330

Gnomad4 NFE

AF:

0.0115

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.00761

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0133

AC:

114

ExAC

AF:

0.00863

AC:

1048

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0155

EpiControl

AF:

0.0171

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Benign:5

Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Apr 03, 2024	NM_000215.4(JAK3):c.2164G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 722 (p.Val722Ile). The filtering allele frequency (the lower threshold of the 95% CI of 12957/1180016) of the c.2164G>A variant in JAK3 is 0.01082 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1). Additionally, 120 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign 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 B2_Supporting (VCEP specifications version 1). -
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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 27, 2022	- -

not provided

Benign:4Other:1

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The JAK3 p.Val722Ile variant was identified in dbSNP (ID: rs3213409), Cosmic (FATHMM predicted neutral; score=0.23), LOVD 3.0 and ClinVar (classified as likely benign by GeneDx and ARUP Laboratories and as benign by Invitae for severe combined immunodeficiency). The variant was also identified in control databases in 2370 of 282750 chromosomes (21 homozygous) at a frequency of 0.008382 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 263 of 10368 chromosomes (freq: 0.02537), European (non-Finnish) in 1573 of 129108 chromosomes (freq: 0.01218), Other in 68 of 7226 chromosomes (freq: 0.00941), Latino in 179 of 35434 chromosomes (freq: 0.005052), South Asian in 143 of 30616 chromosomes (freq: 0.004671), European (Finnish) in 90 of 25118 chromosomes (freq: 0.003583), African in 53 of 24934 chromosomes (freq: 0.002126) and East Asian in 1 of 19946 chromosomes (freq: 0.00005). The V722I variant was identified in the compound heterozygous state in 1/10 patients with severe combined immunodeficiency (SCID) (Roberts_2004_PMID:14615376). Another study identified the variant in the heterozygous state in 1/14 patients with SCID (Schumacher_2000_PMID:10982185). The V722I variant has also been identified somatically in mutliple cancers, including acute myelogenous leukemia, natural killer T-cell lymphoma, acute lymphoblastic leukemia and lung tumors and has been suggested to be an acitivating mutation (Van Allen_2015_PMID:26014096; MacConaill_2014_PMID:25157968; Bergmann_2014_PMID:24446122; Riera_2011_PMID:21599579; Yin_2015_PMID:25146434). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val722 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2021	This variant is associated with the following publications: (PMID: 24728327, 29921932, 10982185, 19282076, 21228398, 26182690, 27884173, 14615376, 33040328) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	JAK3: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

JAK3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2024

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 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

0.071

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.41

T;T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.56

T;.;T

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.80

N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.029

D;D;D

Sift4G

Benign

0.067

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.032

MVP

0.35

MPC

0.39

ClinPred

0.016

GERP RS

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.048

gMVP

0.53

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