rs2230589

Positions:

• chr19-17832574-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1 BP7 BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000215.4(JAK3):c.2625C>T (p.Leu875=) synonymous variant occurs at a high allele frequency with a filtering allele frequency based on the European non-Finnish population (upper bound of 95% CI of 1934/129188 observed alleles) is 0.01456 in gnomAD v2.1.1 which is above the SCID-VCEP threshold (>0.00447; BA1). 17 adult homozygous individuals were reported in gnomAD, BS2_Supporting (European non-Finnish n=10, South Asian n=3, European Finnish n=2, and Other n=2).The variant has been reported in one patient in the literature (Patient 17 in PMID:19203666). Patient 17 has T-B+NK- (0 CD3 T cells, 0.14x10^9 B cells/L, 0.01x10^9 NK cells/L) SCID (0.5pt) and absent IL-2–induced STAT5 phosphorylation (1pt). This combination is specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (Total 1.5pt; PP4 not considered due to high allele frequency). A confirmed deleterious γc or JAK3 variant was not identified in Patient 17, although a number of sequence variants were identified in his JAK3 gene (IVS13-30c>t/wt, c.2625C>T (L875L)/wt, IVS 20+32T>C/wt). An affected sibling of Patient 17 also carried these same variants, whereas an unaffected sibling did not (PP1 not considered due to high allele frequency). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1, BS2_Supporting, and BP7. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214091/MONDO:0010938/121

• Frequency:
  • Genomes: 𝑓 0.0096 (11 hom., cov: 32)
  • Exomes 𝑓: 0.015 (193 hom.)
• Consequence: JAK3 NM_000215.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: -0.0320

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 -10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.2625C>T	p.Leu875=	synonymous_variant	19/24	ENST00000458235.7
JAK3	XM_047438786.1	c.2625C>T	p.Leu875=	synonymous_variant	19/24
JAK3	XR_007066796.1	n.2675C>T		non_coding_transcript_exon_variant	19/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.2625C>T	p.Leu875=	synonymous_variant	19/24	5	NM_000215.4	P1

Frequencies

GnomAD3 genomes AF: 0.00963 AC: 1466 AN: 152222 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00997

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0107 AC: 2700 AN: 251480 Hom.: 16 AF XY: 0.0116 AC XY: 1573 AN XY: 135916

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0136

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0146 AC: 21407 AN: 1461872 Hom.: 193 Cov.: 33 AF XY: 0.0146 AC XY: 10598 AN XY: 727236

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.00409

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0143

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0165

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.00960 AC: 1463 AN: 152340 Hom.: 11 Cov.: 32 AF XY: 0.00925 AC XY: 689 AN XY: 74508

Gnomad4 AFR AF: 0.00325

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.00997

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0123 Hom.: 5

Bravo AF: 0.00884

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0158

EpiControl AF: 0.0161

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

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	Nov 14, 2023	The NM_000215.4(JAK3):c.2625C>T (p.Leu875=) synonymous variant occurs at a high allele frequency with a filtering allele frequency based on the European non-Finnish population (upper bound of 95% CI of 1934/129188 observed alleles) is 0.01456 in gnomAD v2.1.1 which is above the SCID-VCEP threshold (>0.00447; BA1). 17 adult homozygous individuals were reported in gnomAD, BS2_Supporting (European non-Finnish n=10, South Asian n=3, European Finnish n=2, and Other n=2). The variant has been reported in one patient in the literature (Patient 17 in PMID: 19203666). Patient 17 has T-B+NK- (0 CD3 T cells, 0.14x10^9 B cells/L, 0.01x10^9 NK cells/L) SCID (0.5pt) and absent IL-2–induced STAT5 phosphorylation (1pt). This combination is specific for T-B+ severe combined immunodeficiency due to JAK3 deficiency (Total 1.5pt; PP4 not considered due to high allele frequency). A confirmed deleterious γc or JAK3 variant was not identified in Patient 17, although a number of sequence variants were identified in his JAK3 gene (IVS13-30c>t/wt, c.2625C>T (L875L)/wt, IVS 20+32T>C/wt). An affected sibling of Patient 17 also carried these same variants, whereas an unaffected sibling did not (PP1 not considered due to high allele frequency). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1, BS2_Supporting, and BP7. (VCEP specifications version 1). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 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. -

Severe combined immunodeficiency disease Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 29, 2011

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.62

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

Other links and lift over

dbSNP: rs2230589; hg19: chr19-17943383; COSMIC: COSV71685927;