chr19-17844337-A-C

Position:

chr19-17844337-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000215.4(JAK3):c.81T>G(p.His27Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,611,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.57

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 2 ACMG points.

PM1

In a region_of_interest Interaction with cytokine/interferon/growth hormone receptors (size 222) in uniprot entity JAK3_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000215.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.071784645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
JAK3	NM_000215.4 linkuse as main transcript	c.81T>G	p.His27Gln	missense_variant	2/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1 linkuse as main transcript	c.81T>G	p.His27Gln	missense_variant	2/24		XP_047294742.1
JAK3	XM_011527991.3 linkuse as main transcript	c.81T>G	p.His27Gln	missense_variant	2/14		XP_011526293.2
JAK3	XR_007066796.1 linkuse as main transcript	n.131T>G		non_coding_transcript_exon_variant	2/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 linkuse as main transcript	c.81T>G	p.His27Gln	missense_variant	2/24	5	NM_000215.4	ENSP00000391676	P1	P52333-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

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:

0.0000123

AC:

AN:

244632

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133360

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000165

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459478

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725958

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Aug 31, 2021

This sequence change replaces histidine with glutamine at codon 27 of the JAK3 protein (p.His27Gln). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with primary immunodeficiency (PMID: 29049190). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

0.13

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.0010

DANN

Benign

0.25

DEOGEN2

Benign

0.22

T;T;.

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.47

T;.;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.072

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.20

N;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.24

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.55

T;T;T

Sift4G

Benign

0.83

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.14

MutPred

0.37

Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);

MVP

0.46

MPC

0.49

ClinPred

0.010

GERP RS

-11

Varity_R

0.048

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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