rs3008

chr19-17826620-A-G

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.*123T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 1,054,640 control chromosomes in the GnomAD database, including 126,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21277 hom., cov: 31)
  • Exomes 𝑓: 0.48 (105717 hom.)
• Consequence: JAK3 NM_000215.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.568

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=-0.74).
• BP6: Variant 19-17826620-A-G is Benign according to our data. Variant chr19-17826620-A-G is described in ClinVar as [Benign]. Clinvar id is 328495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.*123T>C		3_prime_UTR_variant	24/24	ENST00000458235.7
JAK3	XM_047438786.1	c.*123T>C		3_prime_UTR_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.*123T>C		3_prime_UTR_variant	24/24	5	NM_000215.4	P1

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79281 AN: 151812 Hom.: 21246 Cov.: 31

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.522

GnomAD4 exome AF: 0.482 AC: 435176 AN: 902710 Hom.: 105717 Cov.: 12 AF XY: 0.480 AC XY: 226447 AN XY: 471464

Gnomad4 AFR exome AF: 0.643

Gnomad4 AMR exome AF: 0.591

Gnomad4 ASJ exome AF: 0.502

Gnomad4 EAS exome AF: 0.451

Gnomad4 SAS exome AF: 0.484

Gnomad4 FIN exome AF: 0.519

Gnomad4 NFE exome AF: 0.465

Gnomad4 OTH exome AF: 0.492

GnomAD4 genome AF: 0.522 AC: 79369 AN: 151930 Hom.: 21277 Cov.: 31 AF XY: 0.523 AC XY: 38831 AN XY: 74262

Gnomad4 AFR AF: 0.634

Gnomad4 AMR AF: 0.530

Gnomad4 ASJ AF: 0.504

Gnomad4 EAS AF: 0.452

Gnomad4 SAS AF: 0.477

Gnomad4 FIN AF: 0.509

Gnomad4 NFE AF: 0.466

Gnomad4 OTH AF: 0.521

Alfa AF: 0.493 Hom.: 10293

Bravo AF: 0.531

Asia WGS AF: 0.498 AC: 1732 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. 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 13, 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. -

not provided Benign:1

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	-0.74
Cadd	Benign	3.0
Dann	Benign	0.84

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: rs3008; hg19: chr19-17937429; COSMIC: COSV71687290; COSMIC: COSV71687290;