NM_002227.4:c.7-964T>C

Variant names:

• chr1-64884439-A-G
• rs310199
• NM_002227.4:c.7-964T>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.7-964T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 151,962 control chromosomes in the GnomAD database, including 16,107 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 0.43 (16107 hom., cov: 32)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.904
• Publications: 17 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.655 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.7-964T>C		intron	N/A	NP_002218.2
	JAK1	NM_001320923.2		c.7-964T>C		intron	N/A	NP_001307852.1
	JAK1	NM_001321852.2		c.7-964T>C		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.7-964T>C		intron	N/A	ENSP00000343204.4
	JAK1	ENST00000671929.2		c.7-964T>C		intron	N/A	ENSP00000500485.1
	JAK1	ENST00000671954.2		c.7-964T>C		intron	N/A	ENSP00000500841.1

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64948 AN: 151844 Hom.: 16046 Cov.: 32

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.400

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

GnomAD4 genome AF: 0.428 AC: 65086 AN: 151962 Hom.: 16107 Cov.: 32 AF XY: 0.431 AC XY: 31983 AN XY: 74280

African (AFR) AF: 0.662 AC: 27426 AN: 41454

American (AMR) AF: 0.506 AC: 7728 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1210 AN: 3470

East Asian (EAS) AF: 0.598 AC: 3067 AN: 5130

South Asian (SAS) AF: 0.413 AC: 1985 AN: 4804

European-Finnish (FIN) AF: 0.292 AC: 3078 AN: 10558

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19445 AN: 67956

Other (OTH) AF: 0.407 AC: 857 AN: 2108

Alfa AF: 0.337 Hom.: 32884

Bravo AF: 0.455

Asia WGS AF: 0.547 AC: 1903 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.027
DANN	Benign	0.56
PhyloP100		-0.90
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: rs310199; hg19: chr1-65350122; COSMIC: COSV61097327;