NM_000215.4:c.184+40G>A

Variant names:

• chr19-17844194-C-T
• rs3212712
• NM_000215.4:c.184+40G>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+40G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,539,842 control chromosomes in the GnomAD database, including 85,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15594 hom., cov: 32)
  • Exomes 𝑓: 0.31 (69850 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.74
• Publications: 4 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=-0.89).
• BP6: Variant 19-17844194-C-T is Benign according to our data. Variant chr19-17844194-C-T is described in ClinVar as Benign. ClinVar VariationId is 1291546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.184+40G>A		intron_variant	Intron 2 of 23	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.184+40G>A		intron_variant	Intron 2 of 23		NP_001427368.1
JAK3	XM_011527991.3	c.184+40G>A		intron_variant	Intron 2 of 13		XP_011526293.2
JAK3	XR_007066796.1	n.234+40G>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+40G>A		intron_variant	Intron 2 of 23	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63238 AN: 151832 Hom.: 15562 Cov.: 32

Gnomad AFR AF: 0.699

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.333 AC: 54007 AN: 162192 AF XY: 0.327

Gnomad AFR exome AF: 0.702

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.331

GnomAD4 exome AF: 0.309 AC: 429415 AN: 1387892 Hom.: 69850 Cov.: 28 AF XY: 0.309 AC XY: 211770 AN XY: 686182

African (AFR) AF: 0.711 AC: 22459 AN: 31578

American (AMR) AF: 0.358 AC: 12987 AN: 36258

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 8688 AN: 25120

East Asian (EAS) AF: 0.338 AC: 12250 AN: 36264

South Asian (SAS) AF: 0.331 AC: 26271 AN: 79380

European-Finnish (FIN) AF: 0.228 AC: 10884 AN: 47748

Middle Eastern (MID) AF: 0.334 AC: 1361 AN: 4070

European-Non Finnish (NFE) AF: 0.294 AC: 314875 AN: 1069864

Other (OTH) AF: 0.341 AC: 19640 AN: 57610

GnomAD4 genome AF: 0.417 AC: 63319 AN: 151950 Hom.: 15594 Cov.: 32 AF XY: 0.412 AC XY: 30622 AN XY: 74288

African (AFR) AF: 0.699 AC: 28954 AN: 41422

American (AMR) AF: 0.399 AC: 6093 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1203 AN: 3468

East Asian (EAS) AF: 0.336 AC: 1731 AN: 5152

South Asian (SAS) AF: 0.327 AC: 1580 AN: 4828

European-Finnish (FIN) AF: 0.220 AC: 2322 AN: 10570

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20093 AN: 67938

Other (OTH) AF: 0.420 AC: 888 AN: 2112

Alfa AF: 0.353 Hom.: 3484

Bravo AF: 0.442

Asia WGS AF: 0.371 AC: 1290 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 61% of patients studied by a panel of primary immunodeficiencies. Number of patients: 54. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.4
DANN	Benign	0.63
PhyloP100		-1.7
PromoterAI		0.0020	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: rs3212712; hg19: chr19-17955003; COSMIC: COSV101512871;