Genetic Variant NM_002227.4:c.2049C>A (chr1-64845579-G-T) – 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_002227.4(JAK1):c.2049C>A(p.Ser683Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S683S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

JAK1
NM_002227.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.92

Publications

33 publications found

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]

JAK1 Gene-Disease associations (from GenCC):

autoinflammation, immune dysregulation, and eosinophilia
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

JAK1 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=0.1779949).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JAK1	NM_002227.4	MANE Select	c.2049C>A	p.Ser683Arg	missense	Exon 15 of 25	NP_002218.2	P23458
JAK1	NM_001320923.2		c.2049C>A	p.Ser683Arg	missense	Exon 16 of 26	NP_001307852.1	P23458
JAK1	NM_001321852.2		c.2049C>A	p.Ser683Arg	missense	Exon 15 of 25	NP_001308781.1	P23458

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JAK1	ENST00000342505.5	TSL:5 MANE Select	c.2049C>A	p.Ser683Arg	missense	Exon 15 of 25	ENSP00000343204.4	P23458
JAK1	ENST00000671929.2		c.2049C>A	p.Ser683Arg	missense	Exon 16 of 26	ENSP00000500485.1	P23458
JAK1	ENST00000671954.2		c.2049C>A	p.Ser683Arg	missense	Exon 16 of 26	ENSP00000500841.1	P23458

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.26

CADD

Benign

0.042

(source)

DANN

Benign

0.54

DEOGEN2

Uncertain

0.42

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.75

MutationAssessor

Benign

-0.24

PhyloP100

-1.9

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.72

REVEL

Uncertain

0.43

Sift

Benign

0.66

Sift4G

Benign

0.57

Polyphen

0.97

Vest4

0.18

MutPred

0.42

Gain of MoRF binding (P = 0.0241)

MVP

0.77

MPC

2.3

ClinPred

0.36

GERP RS

-6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.64

Mutation Taster

=69/31

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over