rs310219

Variant names:

• chr1-64849615-C-T
• rs310219
• NM_002227.4:c.1755+1189G>A

Variant summary

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

The NM_002227.4(JAK1):​c.1755+1189G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 152,166 control chromosomes in the GnomAD database, including 11,839 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 0.36 (11839 hom., cov: 33)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 8 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4	c.1755+1189G>A		intron_variant	Intron 12 of 24	ENST00000342505.5	NP_002218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5	c.1755+1189G>A		intron_variant	Intron 12 of 24	5	NM_002227.4	ENSP00000343204.4

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54498 AN: 152048 Hom.: 11793 Cov.: 33

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.338

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

GnomAD4 genome AF: 0.359 AC: 54604 AN: 152166 Hom.: 11839 Cov.: 33 AF XY: 0.357 AC XY: 26545 AN XY: 74398

African (AFR) AF: 0.616 AC: 25555 AN: 41504

American (AMR) AF: 0.309 AC: 4731 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1238 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1527 AN: 5170

South Asian (SAS) AF: 0.229 AC: 1105 AN: 4832

European-Finnish (FIN) AF: 0.286 AC: 3030 AN: 10588

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16465 AN: 67982

Other (OTH) AF: 0.345 AC: 729 AN: 2116

Alfa AF: 0.288 Hom.: 23651

Bravo AF: 0.374

Asia WGS AF: 0.310 AC: 1078 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.46
DANN	Benign	0.53
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs310219; hg19: chr1-65315298;