rs146837396

Positions:

chr19-17834899-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_000215.4(JAK3):c.2152G>C(p.Val718Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000374 in 1,614,188 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 3 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 4.70

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 -7 ACMG points.

PM1

In a domain Protein kinase 1 (size 260) in uniprot entity JAK3_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_000215.4

BP4

Computational evidence support a benign effect (MetaRNN=0.012258768).

BP6

Variant 19-17834899-C-G is Benign according to our data. Variant chr19-17834899-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134572.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, not_provided=1, Uncertain_significance=1}. Variant chr19-17834899-C-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
JAK3	NM_000215.4 linkuse as main transcript	c.2152G>C	p.Val718Leu	missense_variant	16/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1 linkuse as main transcript	c.2152G>C	p.Val718Leu	missense_variant	16/24		XP_047294742.1
JAK3	XR_007066796.1 linkuse as main transcript	n.2202G>C		non_coding_transcript_exon_variant	16/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 linkuse as main transcript	c.2152G>C	p.Val718Leu	missense_variant	16/24	5	NM_000215.4	ENSP00000391676	P1	P52333-1

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000652

AC:

164

AN:

251412

Hom.:

AF XY:

0.000603

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000361

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000355

AC:

519

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

256

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.00478

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000196

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.000552

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000518

Hom.:

Bravo

AF:

0.000786

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000445

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 05, 2017	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.80

T;.;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

N;N;N

MutationTaster

Benign

0.96

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.035

D;D;D

Sift4G

Uncertain

0.057

T;T;T

Polyphen

0.016

B;B;B

Vest4

0.066

MutPred

0.58

Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);

MVP

0.54

MPC

0.90

ClinPred

0.020

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.74

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