rs3008

Variant names:

• chr19-17826620-A-G
• rs3008
• NM_000215.4:c.*123T>C

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -0.568
• Publications: 29 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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.*123T>C		3_prime_UTR_variant	Exon 24 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.*123T>C		3_prime_UTR_variant	Exon 24 of 24		NP_001427368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.*123T>C		3_prime_UTR_variant	Exon 24 of 24	5	NM_000215.4	ENSP00000391676.1

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

African (AFR) AF: 0.643 AC: 14619 AN: 22742

American (AMR) AF: 0.591 AC: 25584 AN: 43262

Ashkenazi Jewish (ASJ) AF: 0.502 AC: 11369 AN: 22650

East Asian (EAS) AF: 0.451 AC: 16734 AN: 37098

South Asian (SAS) AF: 0.484 AC: 36009 AN: 74474

European-Finnish (FIN) AF: 0.519 AC: 26295 AN: 50640

Middle Eastern (MID) AF: 0.516 AC: 2331 AN: 4516

European-Non Finnish (NFE) AF: 0.465 AC: 281531 AN: 605272

Other (OTH) AF: 0.492 AC: 20704 AN: 42056

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

African (AFR) AF: 0.634 AC: 26267 AN: 41434

American (AMR) AF: 0.530 AC: 8071 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 1748 AN: 3470

East Asian (EAS) AF: 0.452 AC: 2330 AN: 5152

South Asian (SAS) AF: 0.477 AC: 2299 AN: 4822

European-Finnish (FIN) AF: 0.509 AC: 5375 AN: 10562

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31646 AN: 67944

Other (OTH) AF: 0.521 AC: 1100 AN: 2110

Alfa AF: 0.505 Hom.: 23177

Bravo AF: 0.531

Asia WGS AF: 0.498 AC: 1732 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.74
CADD	Benign	3.0
DANN	Benign	0.84
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

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