rs310196

Variant names:

• chr1-64885939-A-C
• rs310196
• NM_002227.4:c.6+320T>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.6+320T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 152,162 control chromosomes in the GnomAD database, including 4,877 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 0.21 (4877 hom., cov: 32)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930
• Publications: 7 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: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	NM_002227.4	MANE Select	c.6+320T>G		intron	N/A	NP_002218.2	P23458
	JAK1	NM_001320923.2		c.6+320T>G		intron	N/A	NP_001307852.1	P23458
	JAK1	NM_001321852.2		c.6+320T>G		intron	N/A	NP_001308781.1	P23458

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	ENST00000342505.5	TSL:5 MANE Select	c.6+320T>G		intron	N/A	ENSP00000343204.4	P23458
	JAK1	ENST00000671929.2		c.6+320T>G		intron	N/A	ENSP00000500485.1	P23458
	JAK1	ENST00000671954.2		c.6+320T>G		intron	N/A	ENSP00000500841.1	P23458

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32541 AN: 152044 Hom.: 4851 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.199

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

GnomAD4 genome AF: 0.214 AC: 32615 AN: 152162 Hom.: 4877 Cov.: 32 AF XY: 0.214 AC XY: 15914 AN XY: 74386

African (AFR) AF: 0.417 AC: 17286 AN: 41480

American (AMR) AF: 0.195 AC: 2977 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 688 AN: 3472

East Asian (EAS) AF: 0.280 AC: 1450 AN: 5172

South Asian (SAS) AF: 0.203 AC: 978 AN: 4826

European-Finnish (FIN) AF: 0.132 AC: 1400 AN: 10586

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7367 AN: 68016

Other (OTH) AF: 0.197 AC: 417 AN: 2112

Alfa AF: 0.189 Hom.: 619

Bravo AF: 0.228

Asia WGS AF: 0.258 AC: 898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.9
DANN	Benign	0.35
PhyloP100		-0.093
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs310196;

hg19: chr1-65351622;