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GeneBe

1-64834629-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_002227.4(JAK1):c.3398A>G(p.Glu1133Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

JAK1
NM_002227.4 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.50
Variant links:
Genes affected
JAK1 (HGNC:6190): (Janus kinase 1) This gene encodes a membrane protein that is a member of a class of protein-tyrosine kinases (PTK) characterized by the presence of a second phosphotransferase-related domain immediately N-terminal to the PTK domain. The encoded kinase phosphorylates STAT proteins (signal transducers and activators of transcription) and plays a key role in interferon-alpha/beta, interferon-gamma, and cytokine signal transduction. This gene plays a crucial role in effecting the expression of genes that mediate inflammation, epithelial remodeling, and metastatic cancer progression. This gene is a key component of the interleukin-6 (IL-6)/JAK1/STAT3 immune and inflammation response and is a therapeutic target for alleviating cytokine storms. The kinase activity of this gene is directly inhibited by the suppressor of cytokine signalling 1 (SOCS1) protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2020]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, JAK1

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
JAK1NM_002227.4 linkuse as main transcriptc.3398A>G p.Glu1133Gly missense_variant 25/25 ENST00000342505.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
JAK1ENST00000342505.5 linkuse as main transcriptc.3398A>G p.Glu1133Gly missense_variant 25/255 NM_002227.4 A1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249364
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135300
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
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:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459564
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
726232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 23, 2022This sequence change replaces glutamic acid with glycine at codon 1133 of the JAK1 protein (p.Glu1133Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with JAK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1389319). 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: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). 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
0.32
BayesDel_addAF
Uncertain
0.076
D
BayesDel_noAF
Uncertain
-0.050
Cadd
Uncertain
25
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.070
D
MetaRNN
Uncertain
0.47
T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
1.5
L
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-2.3
N
REVEL
Uncertain
0.54
Sift
Benign
0.052
T
Sift4G
Benign
0.25
T
Polyphen
0.76
P
Vest4
0.32
MutPred
0.41
Loss of ubiquitination at K1130 (P = 0.0578);
MVP
0.78
MPC
1.9
ClinPred
0.74
D
GERP RS
5.0
Varity_R
0.19
gMVP
0.73

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1295192654; hg19: chr1-65300312; API