rs1129739

Variant names:

• chr1-64834649-T-A
• rs1129739
• NM_002227.4:c.3378A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-64834649-T-A
• chr1-64834649-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002227.4(JAK1):​c.3378A>T​(p.Gln1126His) 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. 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. Synonymous variant affecting the same amino acid position (i.e. Q1126Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAK1 NM_002227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.29
• Publications: 4 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: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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=0.1788458).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	NM_002227.4	MANE Select	c.3378A>T	p.Gln1126His	missense	Exon 25 of 25	NP_002218.2	P23458
	JAK1	NM_001320923.2		c.3378A>T	p.Gln1126His	missense	Exon 26 of 26	NP_001307852.1	P23458
	JAK1	NM_001321852.2		c.3378A>T	p.Gln1126His	missense	Exon 25 of 25	NP_001308781.1	P23458

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	ENST00000342505.5	TSL:5 MANE Select	c.3378A>T	p.Gln1126His	missense	Exon 25 of 25	ENSP00000343204.4	P23458
	JAK1	ENST00000671929.2		c.3378A>T	p.Gln1126His	missense	Exon 26 of 26	ENSP00000500485.1	P23458
	JAK1	ENST00000671954.2		c.3378A>T	p.Gln1126His	missense	Exon 26 of 26	ENSP00000500841.1	P23458

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.066
DANN	Benign	0.69
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.71	N
PhyloP100		-3.3
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.28
Sift	Benign	0.24	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.56		Gain of ubiquitination at K1130 (P = 0.0804)
MVP		0.65
MPC		1.0
ClinPred		0.063	T
GERP RS		-10
Varity_R		0.13
gMVP		0.26
Mutation Taster		=52/48	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: rs1129739; hg19: chr1-65300332;