Genetic Variant NM_000215.4:c.23C>T (chr19-17844395-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000215.4(JAK3):c.23C>T(p.Thr8Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000733 in 1,611,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T8T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:2

Conservation

PhyloP100: 2.89

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

T-B+ severe combined immunodeficiency due to JAK3 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

JAK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12151155).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.23C>T	p.Thr8Met	missense	Exon 2 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.23C>T	p.Thr8Met	missense	Exon 2 of 24	NP_001427368.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JAK3	ENST00000458235.7	TSL:5 MANE Select	c.23C>T	p.Thr8Met	missense	Exon 2 of 24	ENSP00000391676.1	P52333-1
JAK3	ENST00000527670.5	TSL:1	c.23C>T	p.Thr8Met	missense	Exon 1 of 23	ENSP00000432511.1	P52333-1
JAK3	ENST00000534444.1	TSL:1	c.23C>T	p.Thr8Met	missense	Exon 2 of 23	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000560

AC:

136

AN:

242704

AF XY:

0.000536

show subpopulations

Gnomad AFR exome

AF:

0.000332

Gnomad AMR exome

AF:

0.000819

Gnomad ASJ exome

AF:

0.000509

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000479

Gnomad NFE exome

AF:

0.000885

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000754

AC:

1100

AN:

1459292

Hom.:

Cov.:

AF XY:

0.000737

AC XY:

535

AN XY:

725812

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33458

American (AMR)

AF:

0.000808

AC:

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.000307

AC:

AN:

26072

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39660

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85938

European-Finnish (FIN)

AF:

0.0000383

AC:

AN:

52166

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000887

AC:

986

AN:

1111398

Other (OTH)

AF:

0.000928

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000538

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41552

American (AMR)

AF:

0.000458

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000926

AC:

AN:

68014

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000806

Hom.:

Bravo

AF:

0.000529

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000819

AC:

ExAC

AF:

0.000595

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

T-B+ severe combined immunodeficiency due to JAK3 deficiency (4)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

0.69

PhyloP100

2.9

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.29

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.21

MVP

0.79

MPC

1.4

ClinPred

0.029

GERP RS

4.2

PromoterAI

-0.0040

Neutral

(source)

Varity_R

0.036

gMVP

0.51

Mutation Taster

=82/18

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over