rs11208538

Variant names:

• chr1-64923606-C-G
• rs11208538
• NM_002227.4:c.-77-37265G>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.-77-37265G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 152,094 control chromosomes in the GnomAD database, including 31,281 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 0.59 (31281 hom., cov: 32)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0840
• Publications: 2 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=-0.58).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4	c.-77-37265G>C		intron_variant	Intron 1 of 24	ENST00000342505.5	NP_002218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5	c.-77-37265G>C		intron_variant	Intron 1 of 24	5	NM_002227.4	ENSP00000343204.4

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89913 AN: 151976 Hom.: 31282 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.818

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.654

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

GnomAD4 genome AF: 0.591 AC: 89905 AN: 152094 Hom.: 31281 Cov.: 32 AF XY: 0.585 AC XY: 43486 AN XY: 74342

African (AFR) AF: 0.241 AC: 10000 AN: 41480

American (AMR) AF: 0.581 AC: 8874 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.818 AC: 2839 AN: 3470

East Asian (EAS) AF: 0.208 AC: 1075 AN: 5172

South Asian (SAS) AF: 0.660 AC: 3184 AN: 4824

European-Finnish (FIN) AF: 0.675 AC: 7126 AN: 10556

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.801 AC: 54470 AN: 68000

Other (OTH) AF: 0.649 AC: 1368 AN: 2108

Alfa AF: 0.686 Hom.: 4879

Bravo AF: 0.564

Asia WGS AF: 0.415 AC: 1448 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.84
PhyloP100		-0.084
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: rs11208538; hg19: chr1-65389289; COSMIC: COSV61089062; COSMIC: COSV61089062;