1-64884134-C-G

Variant names:

• chr1-64884134-C-G
• rs310200
• NM_002227.4:c.7-659G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002227.4(JAK1):​c.7-659G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 151,880 control chromosomes in the GnomAD database, including 13,224 homozygotes. 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: 𝑓 0.37 (13224 hom., cov: 31)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.270
• 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: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.64 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4	c.7-659G>C		intron_variant	Intron 2 of 24	ENST00000342505.5	NP_002218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5	c.7-659G>C		intron_variant	Intron 2 of 24	5	NM_002227.4	ENSP00000343204.4

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56370 AN: 151760 Hom.: 13169 Cov.: 31

Gnomad AFR AF: 0.646

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.345

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.372 AC: 56500 AN: 151880 Hom.: 13224 Cov.: 31 AF XY: 0.374 AC XY: 27735 AN XY: 74242

African (AFR) AF: 0.647 AC: 26759 AN: 41372

American (AMR) AF: 0.351 AC: 5362 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1060 AN: 3470

East Asian (EAS) AF: 0.595 AC: 3064 AN: 5146

South Asian (SAS) AF: 0.352 AC: 1694 AN: 4812

European-Finnish (FIN) AF: 0.258 AC: 2720 AN: 10554

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14841 AN: 67958

Other (OTH) AF: 0.352 AC: 742 AN: 2106

Alfa AF: 0.319 Hom.: 1171

Bravo AF: 0.393

Asia WGS AF: 0.509 AC: 1770 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.4
DANN	Benign	0.39
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs310200; hg19: chr1-65349817;