19-17844192-C-T

Variant names:

• chr19-17844192-C-T
• rs3212713
• NM_000215.4:c.184+42G>A

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.184+42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,535,870 control chromosomes in the GnomAD database, including 76,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10870 hom., cov: 32)
  • Exomes 𝑓: 0.30 (65214 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.254
• Publications: 8 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=-0.8).
• BP6: Variant 19-17844192-C-T is Benign according to our data. Variant chr19-17844192-C-T is described in ClinVar as Benign. ClinVar VariationId is 1291547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.184+42G>A		intron_variant	Intron 2 of 23	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.184+42G>A		intron_variant	Intron 2 of 23		NP_001427368.1
JAK3	XM_011527991.3	c.184+42G>A		intron_variant	Intron 2 of 13		XP_011526293.2
JAK3	XR_007066796.1	n.234+42G>A		intron_variant	Intron 2 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.184+42G>A		intron_variant	Intron 2 of 23	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55343 AN: 151848 Hom.: 10860 Cov.: 32

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.321 AC: 51482 AN: 160416 AF XY: 0.318

Gnomad AFR exome AF: 0.514

Gnomad AMR exome AF: 0.339

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.323

GnomAD4 exome AF: 0.304 AC: 420086 AN: 1383904 Hom.: 65214 Cov.: 28 AF XY: 0.304 AC XY: 207754 AN XY: 684336

African (AFR) AF: 0.523 AC: 16451 AN: 31450

American (AMR) AF: 0.347 AC: 12552 AN: 36148

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 8641 AN: 25096

East Asian (EAS) AF: 0.338 AC: 12215 AN: 36156

South Asian (SAS) AF: 0.331 AC: 26184 AN: 79216

European-Finnish (FIN) AF: 0.228 AC: 10828 AN: 47570

Middle Eastern (MID) AF: 0.318 AC: 1293 AN: 4060

European-Non Finnish (NFE) AF: 0.294 AC: 313125 AN: 1066736

Other (OTH) AF: 0.327 AC: 18797 AN: 57472

GnomAD4 genome AF: 0.364 AC: 55391 AN: 151966 Hom.: 10870 Cov.: 32 AF XY: 0.362 AC XY: 26894 AN XY: 74306

African (AFR) AF: 0.519 AC: 21514 AN: 41416

American (AMR) AF: 0.379 AC: 5784 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1201 AN: 3468

East Asian (EAS) AF: 0.336 AC: 1728 AN: 5142

South Asian (SAS) AF: 0.327 AC: 1578 AN: 4828

European-Finnish (FIN) AF: 0.219 AC: 2321 AN: 10586

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20013 AN: 67950

Other (OTH) AF: 0.378 AC: 799 AN: 2112

Alfa AF: 0.350 Hom.: 11350

Bravo AF: 0.382

Asia WGS AF: 0.357 AC: 1241 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Jun 23, 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 60% of patients studied by a panel of primary immunodeficiencies. Number of patients: 53. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.7
DANN	Benign	0.73
PhyloP100		0.25
PromoterAI		-0.037	Neutral
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: rs3212713; hg19: chr19-17955001; COSMIC: COSV101512869;