dbSNP rs587778415: JAK3:p.Met610Ile (chr19-17836008-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000215.4(JAK3):c.1830G>T(p.Met610Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M610T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.41

Publications

0 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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Orphanet

JAK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16206694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4 link	c.1830G>T	p.Met610Ile	missense_variant	Exon 14 of 24	ENST00000458235.7	NP_000206.2	P52333-1A0A024R7M7
JAK3	NM_001440439.1 link	c.1830G>T	p.Met610Ile	missense_variant	Exon 14 of 24		NP_001427368.1
JAK3	XR_007066796.1 link	n.1880G>T		non_coding_transcript_exon_variant	Exon 14 of 20
JAK3	XM_011527991.3 link	c.*909G>T		downstream_gene_variant			XP_011526293.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7 link	c.1830G>T	p.Met610Ile	missense_variant	Exon 14 of 24	5	NM_000215.4	ENSP00000391676.1		P52333-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.0010

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.35

T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.69

T;.;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.93

L;L;L

PhyloP100

-3.4

PrimateAI

Benign

0.35

PROVEAN

Benign

0.30

N;N;N

REVEL

Benign

0.082

Sift

Benign

0.38

T;T;T

Sift4G

Benign

0.55

T;T;T

Polyphen

0.0040

B;B;B

Vest4

0.18

MutPred

0.51

Gain of catalytic residue at M610 (P = 0.001);Gain of catalytic residue at M610 (P = 0.001);Gain of catalytic residue at M610 (P = 0.001);

MVP

0.52

MPC

0.53

ClinPred

0.19

GERP RS

-9.9

Varity_R

0.051

gMVP

0.60

Mutation Taster

=90/10

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over