rs7250423

Variant names:

• chr19-17847808-C-T
• rs7250423
• NM_000215.4:c.-14+138G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000215.4(JAK3):​c.-14+138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 239,806 control chromosomes in the GnomAD database, including 7,794 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (7224 hom., cov: 33)
  • Exomes 𝑓: 0.085 (570 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.40
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.554 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.-14+138G>A		intron	N/A	NP_000206.2
	JAK3	NM_001440439.1		c.-45+138G>A		intron	N/A	NP_001427368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.-14+138G>A		intron	N/A	ENSP00000391676.1	P52333-1
	JAK3	ENST00000534444.1	TSL:1	c.-14+138G>A		intron	N/A	ENSP00000436421.1	P52333-2
	JAK3	ENST00000526008.6	TSL:2	n.-14+138G>A		intron	N/A	ENSP00000513006.1	A0A0S2Z4R7

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33362 AN: 152146 Hom.: 7205 Cov.: 33

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0738

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.0853 AC: 7468 AN: 87546 Hom.: 570 AF XY: 0.0818 AC XY: 3370 AN XY: 41208

African (AFR) AF: 0.534 AC: 901 AN: 1688

American (AMR) AF: 0.129 AC: 79 AN: 612

Ashkenazi Jewish (ASJ) AF: 0.0884 AC: 176 AN: 1990

East Asian (EAS) AF: 0.205 AC: 1164 AN: 5686

South Asian (SAS) AF: 0.0699 AC: 97 AN: 1388

European-Finnish (FIN) AF: 0.0435 AC: 2 AN: 46

Middle Eastern (MID) AF: 0.0973 AC: 29 AN: 298

European-Non Finnish (NFE) AF: 0.0632 AC: 4532 AN: 71728

Other (OTH) AF: 0.119 AC: 488 AN: 4110

GnomAD4 genome AF: 0.220 AC: 33434 AN: 152260 Hom.: 7224 Cov.: 33 AF XY: 0.217 AC XY: 16125 AN XY: 74450

African (AFR) AF: 0.560 AC: 23239 AN: 41504

American (AMR) AF: 0.149 AC: 2276 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 358 AN: 3468

East Asian (EAS) AF: 0.223 AC: 1152 AN: 5176

South Asian (SAS) AF: 0.117 AC: 563 AN: 4830

European-Finnish (FIN) AF: 0.0325 AC: 345 AN: 10624

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0737 AC: 5017 AN: 68036

Other (OTH) AF: 0.194 AC: 411 AN: 2116

Alfa AF: 0.124 Hom.: 2816

Bravo AF: 0.243

Asia WGS AF: 0.205 AC: 712 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.43
DANN	Benign	0.79
PhyloP100		-3.4
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs7250423; hg19: chr19-17958617;