rs3212752

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000215.4(JAK3):c.1701+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 1,613,714 control chromosomes in the GnomAD database, including 6,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1473 hom., cov: 31)

Exomes 𝑓: 0.072 ( 4644 hom. )

Consequence

JAK3
NM_000215.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.218

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 19-17837923-T-C is Benign according to our data. Variant chr19-17837923-T-C is described in ClinVar as [Benign]. Clinvar id is 137597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
JAK3	NM_000215.4 linkuse as main transcript	c.1701+9A>G	intron_variant	ENST00000458235.7
JAK3	XM_011527991.3 linkuse as main transcript	c.1701+9A>G	intron_variant
JAK3	XM_047438786.1 linkuse as main transcript	c.1701+9A>G	intron_variant
JAK3	XR_007066796.1 linkuse as main transcript	n.1751+9A>G	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7 linkuse as main transcript	c.1701+9A>G		intron_variant		5	NM_000215.4	P1	P52333-1

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

17917

AN:

151894

Hom.:

1466

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0892

Gnomad ASJ

AF:

0.0363

Gnomad EAS

AF:

0.0577

Gnomad SAS

AF:

0.0720

Gnomad FIN

AF:

0.0970

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0718

Gnomad OTH

AF:

0.106

GnomAD3 exomes

AF:

0.0794

AC:

19980

AN:

251490

Hom.:

1127

AF XY:

0.0770

AC XY:

10460

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.234

Gnomad AMR exome

AF:

0.0557

Gnomad ASJ exome

AF:

0.0419

Gnomad EAS exome

AF:

0.0564

Gnomad SAS exome

AF:

0.0700

Gnomad FIN exome

AF:

0.0949

Gnomad NFE exome

AF:

0.0716

Gnomad OTH exome

AF:

0.0723

GnomAD4 exome

AF:

0.0719

AC:

105131

AN:

1461702

Hom.:

4644

Cov.:

AF XY:

0.0714

AC XY:

51885

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.244

Gnomad4 AMR exome

AF:

0.0571

Gnomad4 ASJ exome

AF:

0.0401

Gnomad4 EAS exome

AF:

0.0481

Gnomad4 SAS exome

AF:

0.0740

Gnomad4 FIN exome

AF:

0.0958

Gnomad4 NFE exome

AF:

0.0674

Gnomad4 OTH exome

AF:

0.0771

GnomAD4 genome

AF:

0.118

AC:

17962

AN:

152012

Hom.:

1473

Cov.:

AF XY:

0.118

AC XY:

8741

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.233

Gnomad4 AMR

AF:

0.0891

Gnomad4 ASJ

AF:

0.0363

Gnomad4 EAS

AF:

0.0573

Gnomad4 SAS

AF:

0.0716

Gnomad4 FIN

AF:

0.0970

Gnomad4 NFE

AF:

0.0718

Gnomad4 OTH

AF:

0.110

Alfa

AF:

0.0799

Hom.:

972

Bravo

AF:

0.119

Asia WGS

AF:

0.108

AC:

375

AN:

3478

EpiCase

AF:

0.0636

EpiControl

AF:

0.0635

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 28, 2017	Variant summary: The JAK3 c.1701+9A>G intronic variant involves the alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 23471/277188 control chromosomes (1409 homozygotes) at a frequency of 0.0846754, which is approximately 78 times the estimated maximal expected allele frequency of a pathogenic JAK3 variant (0.0010801), suggesting this variant is likely a benign polymorphism. This variant has been reported in 2 patients with SCID (Walshe 2009), however without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

Cadd

Benign

3.6

Dann

Benign

0.46

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over