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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), 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.

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.*123T>C		3_prime_UTR	Exon 24 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.*123T>C		3_prime_UTR	Exon 24 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.*123T>C		3_prime_UTR	Exon 24 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000527670.5	TSL:1	c.*123T>C		3_prime_UTR	Exon 23 of 23	ENSP00000432511.1	P52333-1
	JAK3	ENST00000526008.6	TSL:2	n.*2055T>C		non_coding_transcript_exon	Exon 25 of 25	ENSP00000513006.1	A0A0S2Z4R7

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	T-B+ severe combined immunodeficiency due to JAK3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

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;