19-17843141-G-C

Position:

chr19-17843141-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000215.4(JAK3):c.452C>G (p.Pro151Arg) variant in JAK3 is a missense variant predicted to cause the substitution of Proline by Arginine at amino acid 151 (p.Pro151Arg). The Popmax Filtering allele frequency (95% CI) of the variant is 0.008679 in gnomAD v.4 for European (non-Finnish) population 10486/1179548 alleles, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, therefore, meets this criterion (BA1). Also, 59 homozygous adults are reported on GnomAD v2.1.1 (BS2_Supporting). 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/CA160252/MONDO:0010938/121

Frequency

Genomes: 𝑓 0.0064 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 52 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:7O:1

Conservation

PhyloP100: -0.433

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BS2

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
JAK3	NM_000215.4 linkuse as main transcript	c.452C>G	p.Pro151Arg	missense_variant	5/24	ENST00000458235.7
JAK3	XM_047438786.1 linkuse as main transcript	c.452C>G	p.Pro151Arg	missense_variant	5/24
JAK3	XM_011527991.3 linkuse as main transcript	c.452C>G	p.Pro151Arg	missense_variant	5/14
JAK3	XR_007066796.1 linkuse as main transcript	n.502C>G		non_coding_transcript_exon_variant	5/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7 linkuse as main transcript	c.452C>G	p.Pro151Arg	missense_variant	5/24	5	NM_000215.4	P1	P52333-1

Frequencies

GnomAD3 genomes

AF:

0.00642

AC:

977

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00289

Gnomad FIN

AF:

0.0107

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.00994

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00592

AC:

1400

AN:

236668

Hom.:

AF XY:

0.00626

AC XY:

817

AN XY:

130472

show subpopulations

Gnomad AFR exome

AF:

0.000891

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00336

Gnomad FIN exome

AF:

0.0114

Gnomad NFE exome

AF:

0.00820

Gnomad OTH exome

AF:

0.00719

GnomAD4 exome

AF:

0.00791

AC:

11511

AN:

1455712

Hom.:

Cov.:

AF XY:

0.00782

AC XY:

5668

AN XY:

724368

show subpopulations

Gnomad4 AFR exome

AF:

0.00123

Gnomad4 AMR exome

AF:

0.00231

Gnomad4 ASJ exome

AF:

0.00859

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00375

Gnomad4 FIN exome

AF:

0.00966

Gnomad4 NFE exome

AF:

0.00883

Gnomad4 OTH exome

AF:

0.00767

GnomAD4 genome

AF:

0.00642

AC:

978

AN:

152292

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

506

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0107

Gnomad4 NFE

AF:

0.00994

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00840

Hom.:

Bravo

AF:

0.00552

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00722

AC:

ExAC

AF:

0.00549

AC:

663

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0119

EpiControl

AF:

0.00838

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 23, 2024	The NM_000215.4(JAK3):c.452C>G (p.Pro151Arg) variant in JAK3 is a missense variant predicted to cause the substitution of Proline by Arginine at amino acid 151 (p.Pro151Arg). The Popmax Filtering allele frequency (95% CI) of the variant is 0.008679 in gnomAD v.4 for European (non-Finnish) population 10486/1179548 alleles, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, therefore, meets this criterion (BA1). Also, 59 homozygous adults are reported on GnomAD v2.1.1 (BS2_Supporting). 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). -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2018	This variant is associated with the following publications: (PMID: 25333069, 21228398, 26248889, 27484032, 11668610, 24728327, 10982185, 27577878, 27151993, 27884173) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 06, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	JAK3: BP4, BS2 -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2022	Variant summary: JAK3 c.452C>G (p.Pro151Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0061 in 269660 control chromosomes, predominantly at a frequency of 0.011 within the Non-Finnish European subpopulation in the gnomAD database, including five homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in JAK3 causing Severe Combined Immunodeficiency phenotype (0.00094), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.452C>G has been reported in the literature in at least one individual affected with Severe Combined Immunodeficiency (Schumacher_2000). The report does not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. Five ClinVar submitters (evaluation after 2014) cite the variant as benign (n=4) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 heterozygote individual with SCID (Schumacher 2000). 1.3% frequency. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

6.3

DANN

Benign

0.87

DEOGEN2

Uncertain

0.56

D;D;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.36

T;.;T

MetaRNN

Benign

0.0096

T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.6

L;L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Uncertain

0.45

Sift

Benign

0.074

T;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.20

MVP

0.98

MPC

0.51

ClinPred

0.013

GERP RS

-4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.78

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

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