rs373046546

Positions:

chr19-17841389-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000215.4(JAK3):c.1142C>A(p.Thr381Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000226 in 1,548,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

JAK3
NM_000215.4 missense, splice_region

Scores

Splicing: ADA: 0.7916

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 3.99

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:

JAK3 (HGNC:):

JAK3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31364527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4 linkuse as main transcript	c.1142C>A	p.Thr381Asn	missense_variant, splice_region_variant	8/24	ENST00000458235.7	NP_000206.2	P52333-1A0A024R7M7
JAK3	XM_047438786.1 linkuse as main transcript	c.1142C>A	p.Thr381Asn	missense_variant, splice_region_variant	8/24		XP_047294742.1
JAK3	XM_011527991.3 linkuse as main transcript	c.1142C>A	p.Thr381Asn	missense_variant, splice_region_variant	8/14		XP_011526293.2
JAK3	XR_007066796.1 linkuse as main transcript	n.1192C>A		splice_region_variant, non_coding_transcript_exon_variant	8/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 linkuse as main transcript	c.1142C>A	p.Thr381Asn	missense_variant, splice_region_variant	8/24	5	NM_000215.4	ENSP00000391676.1		P52333-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.0000129

AC:

AN:

1396780

Hom.:

Cov.:

AF XY:

0.0000102

AC XY:

AN XY:

689374

show subpopulations

Gnomad4 AFR exome

AF:

0.000503

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:

0.00

Gnomad4 OTH exome

AF:

0.0000344

GnomAD4 genome

AF:

0.000112

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.00

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

Alfa

AF:

0.000195

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.000231

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000274

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other: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

Aug 16, 2022

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 381 of the JAK3 protein (p.Thr381Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 134584). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

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

0.26

BayesDel_addAF

Benign

0.00097

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;T;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.84

T;.;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.4

N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.15

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.96

D;D;D

Vest4

0.37

MVP

0.65

MPC

1.2

ClinPred

0.19

GERP RS

4.7

Varity_R

0.23

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.79

dbscSNV1_RF

Benign

0.51

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