NM_002227.4:c.3398A>C

Variant names:

• chr1-64834629-T-G
• rs1295192654
• NM_002227.4:c.3398A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002227.4(JAK1):​c.3398A>C​(p.Glu1133Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1133G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAK1 NM_002227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.50
• Publications: 0 publications found

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: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2907729).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4	c.3398A>C	p.Glu1133Ala	missense_variant	Exon 25 of 25	ENST00000342505.5	NP_002218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5	c.3398A>C	p.Glu1133Ala	missense_variant	Exon 25 of 25	5	NM_002227.4	ENSP00000343204.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.20
Eigen_PC	Benign	0.025
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.015	N
PhyloP100		5.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.31
Sift	Benign	0.28	T
Sift4G	Benign	0.71	T
Polyphen		0.17	B
Vest4		0.31
MutPred		0.46		Loss of ubiquitination at K1130 (P = 0.0618);
MVP		0.72
MPC		1.4
ClinPred		0.45	T
GERP RS		5.0
Varity_R		0.21
gMVP		0.65
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs1295192654; hg19: chr1-65300312; COSMIC: COSV53812149; COSMIC: COSV53812149;