rs7254346

Positions:

• chr19-17847968-T-C

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.-36A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,036,266 control chromosomes in the GnomAD database, including 13,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (7265 hom., cov: 33)
  • Exomes 𝑓: 0.091 (6226 hom.)
• Consequence: JAK3 NM_000215.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.861

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-17847968-T-C is Benign according to our data. Variant chr19-17847968-T-C is described in ClinVar as [Benign]. Clinvar id is 328525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.-36A>G		5_prime_UTR_variant	1/24	ENST00000458235.7	NP_000206.2
JAK3	XM_011527991.3	c.-36A>G		5_prime_UTR_variant	1/14		XP_011526293.2
JAK3	XM_047438786.1	c.-67A>G		5_prime_UTR_variant	1/24		XP_047294742.1
JAK3	XR_007066796.1	n.15A>G		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.-36A>G		5_prime_UTR_variant	1/24	5	NM_000215.4	ENSP00000391676	P1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33472 AN: 152060 Hom.: 7242 Cov.: 33

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0746

Gnomad OTH AF: 0.193

GnomAD4 exome AF: 0.0911 AC: 80578 AN: 884088 Hom.: 6226 Cov.: 29 AF XY: 0.0900 AC XY: 36732 AN XY: 408346

Gnomad4 AFR exome AF: 0.588

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.212

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.0472

Gnomad4 NFE exome AF: 0.0763

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.220 AC: 33553 AN: 152178 Hom.: 7265 Cov.: 33 AF XY: 0.217 AC XY: 16178 AN XY: 74400

Gnomad4 AFR AF: 0.561

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.0325

Gnomad4 NFE AF: 0.0746

Gnomad4 OTH AF: 0.196

Alfa AF: 0.101 Hom.: 1940

Bravo AF: 0.243

Asia WGS AF: 0.206 AC: 715 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

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 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

T-B+ severe combined immunodeficiency due to JAK3 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.0
DANN	Benign	0.35

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: rs7254346; hg19: chr19-17958777;