rs2072496

Positions:

• chr19-17835245-G-A
• chr19-17835245-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000215.4(JAK3):​c.1915-30C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,609,508 control chromosomes in the GnomAD database, including 10,585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (959 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9626 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.40

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 19-17835245-G-A is Benign according to our data. Variant chr19-17835245-G-A is described in ClinVar as [Benign]. Clinvar id is 632862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.1915-30C>T		intron_variant		ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.1915-30C>T		intron_variant			XP_047294742.1
JAK3	XR_007066796.1	n.1965-30C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.1915-30C>T		intron_variant		5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15779 AN: 152174 Hom.: 960 Cov.: 32

Gnomad AFR AF: 0.0985

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.0930

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0545

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0971

GnomAD3 exomes AF: 0.113 AC: 27237 AN: 242044 Hom.: 1818 AF XY: 0.114 AC XY: 15084 AN XY: 132028

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.0895

Gnomad ASJ exome AF: 0.0571

Gnomad EAS exome AF: 0.276

Gnomad SAS exome AF: 0.137

Gnomad FIN exome AF: 0.0612

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.110 AC: 160496 AN: 1457218 Hom.: 9626 Cov.: 39 AF XY: 0.111 AC XY: 80326 AN XY: 724770

Gnomad4 AFR exome AF: 0.0989

Gnomad4 AMR exome AF: 0.0882

Gnomad4 ASJ exome AF: 0.0553

Gnomad4 EAS exome AF: 0.261

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.0584

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.104 AC: 15784 AN: 152290 Hom.: 959 Cov.: 32 AF XY: 0.102 AC XY: 7596 AN XY: 74462

Gnomad4 AFR AF: 0.0984

Gnomad4 AMR AF: 0.0930

Gnomad4 ASJ AF: 0.0576

Gnomad4 EAS AF: 0.271

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.0545

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.0975

Alfa AF: 0.103 Hom.: 478

Bravo AF: 0.106

Asia WGS AF: 0.184 AC: 639 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 28, 2017	Variant summary: The JAK3 c.1915-30C>T variant involves the alteration of a non-conserved intronic nucleotide and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 29715/269050 control chromosomes (1955 homozygotes)(gnomAD) at a frequency of 0.1104442, which is approximately 102 times the estimated maximal expected allele frequency of a pathogenic JAK3 variant (0.0010801), suggesting this variant is likely a benign polymorphism. This variant has been reported in 2 patients with SCID (Walshe 2009), however without strong evidence for causality. Taken together, this variant is classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.4
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2072496; hg19: chr19-17946054; COSMIC: COSV71685824; COSMIC: COSV71685824;