19-17830485-T-C

Variant names:

• chr19-17830485-T-C
• rs2302603
• NM_000215.4:c.3096+18A>G

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.3096+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,594,026 control chromosomes in the GnomAD database, including 93,618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10239 hom., cov: 29)
  • Exomes 𝑓: 0.34 (83379 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.50
• Publications: 10 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=-0.85).
• BP6: Variant 19-17830485-T-C is Benign according to our data. Variant chr19-17830485-T-C is described in CliVar as Benign. Clinvar id is 36421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17830485-T-C is described in CliVar as Benign. Clinvar id is 36421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17830485-T-C is described in CliVar as Benign. Clinvar id is 36421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17830485-T-C is described in CliVar as Benign. Clinvar id is 36421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17830485-T-C is described in CliVar as Benign. Clinvar id is 36421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.3096+18A>G		intron_variant	Intron 22 of 23	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.3096+18A>G		intron_variant	Intron 22 of 23		NP_001427368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.3096+18A>G		intron_variant	Intron 22 of 23	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.363 AC: 54911 AN: 151274 Hom.: 10212 Cov.: 29

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.349

GnomAD2 exomes AF: 0.377 AC: 90497 AN: 239804 AF XY: 0.371

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.512

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.462

Gnomad FIN exome AF: 0.343

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.337 AC: 485561 AN: 1442632 Hom.: 83379 Cov.: 29 AF XY: 0.338 AC XY: 242896 AN XY: 718440

African (AFR) AF: 0.408 AC: 13496 AN: 33062

American (AMR) AF: 0.504 AC: 21914 AN: 43516

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 7071 AN: 26012

East Asian (EAS) AF: 0.436 AC: 17187 AN: 39454

South Asian (SAS) AF: 0.412 AC: 35287 AN: 85574

European-Finnish (FIN) AF: 0.343 AC: 18196 AN: 53090

Middle Eastern (MID) AF: 0.349 AC: 1993 AN: 5704

European-Non Finnish (NFE) AF: 0.319 AC: 349352 AN: 1096522

Other (OTH) AF: 0.353 AC: 21065 AN: 59698

GnomAD4 genome AF: 0.363 AC: 54987 AN: 151394 Hom.: 10239 Cov.: 29 AF XY: 0.363 AC XY: 26855 AN XY: 73936

African (AFR) AF: 0.407 AC: 16799 AN: 41284

American (AMR) AF: 0.414 AC: 6310 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 913 AN: 3458

East Asian (EAS) AF: 0.459 AC: 2318 AN: 5050

South Asian (SAS) AF: 0.426 AC: 2041 AN: 4786

European-Finnish (FIN) AF: 0.346 AC: 3652 AN: 10550

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21798 AN: 67738

Other (OTH) AF: 0.358 AC: 754 AN: 2104

Alfa AF: 0.347 Hom.: 4353

Bravo AF: 0.370

Asia WGS AF: 0.483 AC: 1675 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 69% of patients studied by a panel of primary immunodeficiencies. Number of patients: 61. Only high quality variants are reported. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe combined immunodeficiency disease Benign:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.3
DANN	Benign	0.48
PhyloP100		-1.5
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: rs2302603; hg19: chr19-17941294; COSMIC: COSV71685377;