chr1-64834564-A-C

Variant names:

• chr1-64834564-A-C
• rs200563303
• NM_002227.4:c.3463T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_002227.4(JAK1):​c.3463T>G​(p.Ter1155Gluext*?) variant causes a stop lost 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAK1 NM_002227.4 stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.979
• Publications: 2 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_002227.4 Downstream stopcodon found after 75 codons.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	NM_002227.4	MANE Select	c.3463T>G	p.Ter1155Gluext*?	stop_lost	Exon 25 of 25	NP_002218.2
	JAK1	NM_001320923.2		c.3463T>G	p.Ter1155Gluext*?	stop_lost	Exon 26 of 26	NP_001307852.1
	JAK1	NM_001321852.2		c.3463T>G	p.Ter1155Gluext*?	stop_lost	Exon 25 of 25	NP_001308781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	ENST00000342505.5	TSL:5 MANE Select	c.3463T>G	p.Ter1155Gluext*?	stop_lost	Exon 25 of 25	ENSP00000343204.4
	JAK1	ENST00000671929.2		c.3463T>G	p.Ter1155Gluext*?	stop_lost	Exon 26 of 26	ENSP00000500485.1
	JAK1	ENST00000671954.2		c.3463T>G	p.Ter1155Gluext*?	stop_lost	Exon 26 of 26	ENSP00000500841.1

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
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.87
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		0.98
Vest4		0.12
GERP RS		3.1
Mutation Taster		=163/37	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: rs200563303; hg19: chr1-65300247;