rs55778349

Positions:

• chr19-17843141-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BS2_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
• Clinical Significance: Benign reviewed by expert panel U:1 B:7 O:1
• Conservation: PhyloP100: -0.433

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.452C>G	p.Pro151Arg	missense_variant	5/24	ENST00000458235.7
JAK3	XM_047438786.1	c.452C>G	p.Pro151Arg	missense_variant	5/24
JAK3	XM_011527991.3	c.452C>G	p.Pro151Arg	missense_variant	5/14
JAK3	XR_007066796.1	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	c.452C>G	p.Pro151Arg	missense_variant	5/24	5	NM_000215.4	P1

Frequencies

GnomAD3 genomes AF: 0.00642 AC: 977 AN: 152174 Hom.: 7 Cov.: 32

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.: 4 AF XY: 0.00626 AC XY: 817 AN XY: 130472

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.: 52 Cov.: 33 AF XY: 0.00782 AC XY: 5668 AN XY: 724368

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.: 7 Cov.: 32 AF XY: 0.00680 AC XY: 506 AN XY: 74466

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.: 8

Bravo AF: 0.00552

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00722 AC: 62

ExAC AF: 0.00549 AC: 663

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.00838

ClinVar

Significance: Benign

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

Revision: reviewed by expert panel

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency Uncertain:1 Benign: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:2 Other: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	T
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	N
LIST_S2	Benign	0.36	T;.;T
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
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	T
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

Other links and lift over

dbSNP: rs55778349; hg19: chr19-17953950; COSMIC: COSV71686683; COSMIC: COSV71686683;