rs310214

Variant names:

• chr1-64851630-T-C
• rs310214
• NM_002227.4:c.1649-720A>G

Variant summary

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

The NM_002227.4(JAK1):​c.1649-720A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 152,054 control chromosomes in the GnomAD database, including 14,446 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 0.41 (14446 hom., cov: 32)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.174
• Publications: 1 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

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.1649-720A>G		intron	N/A	NP_002218.2
	JAK1	NM_001320923.2		c.1649-720A>G		intron	N/A	NP_001307852.1
	JAK1	NM_001321852.2		c.1649-720A>G		intron	N/A	NP_001308781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	ENST00000342505.5	TSL:5 MANE Select	c.1649-720A>G		intron	N/A	ENSP00000343204.4
	JAK1	ENST00000671929.2		c.1649-720A>G		intron	N/A	ENSP00000500485.1
	JAK1	ENST00000671954.2		c.1649-720A>G		intron	N/A	ENSP00000500841.1

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62569 AN: 151936 Hom.: 14395 Cov.: 32

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.386

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

GnomAD4 genome AF: 0.412 AC: 62682 AN: 152054 Hom.: 14446 Cov.: 32 AF XY: 0.411 AC XY: 30564 AN XY: 74308

African (AFR) AF: 0.628 AC: 26047 AN: 41492

American (AMR) AF: 0.452 AC: 6900 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1360 AN: 3466

East Asian (EAS) AF: 0.308 AC: 1586 AN: 5156

South Asian (SAS) AF: 0.292 AC: 1408 AN: 4822

European-Finnish (FIN) AF: 0.327 AC: 3452 AN: 10562

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20814 AN: 67966

Other (OTH) AF: 0.392 AC: 827 AN: 2110

Alfa AF: 0.401 Hom.: 1733

Bravo AF: 0.432

Asia WGS AF: 0.340 AC: 1184 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.35
PhyloP100		0.17
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: rs310214; hg19: chr1-65317313;