rs202021264

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The NM_002227.4(JAK1):ā€‹c.184A>Gā€‹(p.Ile62Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000483 in 1,614,016 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…).

Frequency

Genomes: š‘“ 0.00043 ( 0 hom., cov: 32)
Exomes š‘“: 0.00049 ( 2 hom. )

Consequence

JAK1
NM_002227.4 missense

Scores

1
18

Clinical Significance

Benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 1.89
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), JAK1. . Gene score misZ 4.6073 (greater than the threshold 3.09). Trascript score misZ 5.8568 (greater than threshold 3.09). GenCC has associacion of gene with autoinflammation, immune dysregulation, and eosinophilia.
BP4
Computational evidence support a benign effect (MetaRNN=0.008037269).
BP6
Variant 1-64883298-T-C is Benign according to our data. Variant chr1-64883298-T-C is described in ClinVar as [Benign]. Clinvar id is 134548.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 65 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
JAK1NM_002227.4 linkuse as main transcriptc.184A>G p.Ile62Val missense_variant 3/25 ENST00000342505.5 NP_002218.2 P23458

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
JAK1ENST00000342505.5 linkuse as main transcriptc.184A>G p.Ile62Val missense_variant 3/255 NM_002227.4 ENSP00000343204.4 P23458

Frequencies

GnomAD3 genomes
AF:
0.000427
AC:
65
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00720
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000456
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000725
AC:
180
AN:
248442
Hom.:
1
AF XY:
0.000675
AC XY:
91
AN XY:
134808
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.000696
Gnomad ASJ exome
AF:
0.00976
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000445
Gnomad OTH exome
AF:
0.000993
GnomAD4 exome
AF:
0.000489
AC:
715
AN:
1461692
Hom.:
2
Cov.:
31
AF XY:
0.000481
AC XY:
350
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000783
Gnomad4 ASJ exome
AF:
0.0115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000264
Gnomad4 OTH exome
AF:
0.00109
GnomAD4 genome
AF:
0.000427
AC:
65
AN:
152324
Hom.:
0
Cov.:
32
AF XY:
0.000430
AC XY:
32
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00720
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000456
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.00104
Hom.:
3
Bravo
AF:
0.000536
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000255
AC:
1
ESP6500EA
AF:
0.000604
AC:
5
ExAC
AF:
0.000612
AC:
74
EpiCase
AF:
0.000873
EpiControl
AF:
0.000653

ClinVar

Significance: Benign
Submissions summary: Benign:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 13, 2023- -
not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
16
DANN
Benign
0.94
DEOGEN2
Benign
0.28
T
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.32
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.81
T
M_CAP
Benign
0.0089
T
MetaRNN
Benign
0.0080
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L
PrimateAI
Benign
0.47
T
PROVEAN
Benign
0.010
N
REVEL
Benign
0.030
Sift
Benign
0.41
T
Sift4G
Benign
0.49
T
Polyphen
0.010
B
Vest4
0.21
MVP
0.49
MPC
0.49
ClinPred
0.0074
T
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.053
gMVP
0.21

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: rs202021264; hg19: chr1-65348981; COSMIC: COSV99071479; COSMIC: COSV99071479; API