rs2230589

Variant names:

• chr19-17832574-G-A
• rs2230589
• NM_000215.4:c.2625C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-17832574-G-A
• chr19-17832574-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BS2_Supporting BA1

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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• T-B+ severe combined immunodeficiency due to JAK3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.2625C>T	p.Leu875Leu	synonymous	Exon 19 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.2625C>T	p.Leu875Leu	synonymous	Exon 19 of 24	NP_001427368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.2625C>T	p.Leu875Leu	synonymous	Exon 19 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000527670.5	TSL:1	c.2625C>T	p.Leu875Leu	synonymous	Exon 18 of 23	ENSP00000432511.1	P52333-1
	JAK3	ENST00000534444.1	TSL:1	c.2625C>T	p.Leu875Leu	synonymous	Exon 19 of 23	ENSP00000436421.1	P52333-2

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

GnomAD2 exomes AF: 0.0107 AC: 2700 AN: 251480 AF XY: 0.0116

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 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

African (AFR) AF: 0.00263 AC: 88 AN: 33480

American (AMR) AF: 0.00409 AC: 183 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 113 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0143 AC: 1236 AN: 86258

European-Finnish (FIN) AF: 0.0116 AC: 618 AN: 53420

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5768

European-Non Finnish (NFE) AF: 0.0165 AC: 18378 AN: 1111990

Other (OTH) AF: 0.0118 AC: 711 AN: 60396

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

African (AFR) AF: 0.00325 AC: 135 AN: 41584

American (AMR) AF: 0.00582 AC: 89 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4830

European-Finnish (FIN) AF: 0.00997 AC: 106 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0153 AC: 1042 AN: 68028

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	T-B+ severe combined immunodeficiency due to JAK3 deficiency (3)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.62
PhyloP100		-0.032
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2230589; hg19: chr19-17943383;