rs200112185

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000215.4(JAK3):c.1471G>C(p.Gly491Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.68

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.107286096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
JAK3	NM_000215.4 linkuse as main transcript	c.1471G>C	p.Gly491Arg	missense_variant	11/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1 linkuse as main transcript	c.1471G>C	p.Gly491Arg	missense_variant	11/24		XP_047294742.1
JAK3	XM_011527991.3 linkuse as main transcript	c.1471G>C	p.Gly491Arg	missense_variant	11/14		XP_011526293.2
JAK3	XR_007066796.1 linkuse as main transcript	n.1521G>C		non_coding_transcript_exon_variant	11/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 linkuse as main transcript	c.1471G>C	p.Gly491Arg	missense_variant	11/24	5	NM_000215.4	ENSP00000391676	P1	P52333-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251494

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000151

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.000531

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000159

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2022

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 491 of the JAK3 protein (p.Gly491Arg). This variant is present in population databases (rs200112185, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with JAK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 532745). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt JAK3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

T;T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.81

T;.;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.1

L;L;L

MutationTaster

Benign

0.83

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.1

N;N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.029

D;D;D

Polyphen

0.039

B;B;B

Vest4

0.24

MVP

0.82

MPC

1.0

ClinPred

0.11

GERP RS

4.7

Varity_R

0.15

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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