rs2780900

Positions:

• chr1-64852831-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002227.4(JAK1):​c.1649-1921C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,112 control chromosomes in the GnomAD database, including 1,471 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 0.12 (1471 hom., cov: 32)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.48

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]

ACMG classification

Verdict is Benign. Variant got -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 = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK1	NM_002227.4	c.1649-1921C>A		intron_variant		ENST00000342505.5	NP_002218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5	c.1649-1921C>A		intron_variant		5	NM_002227.4	ENSP00000343204	A1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18978 AN: 151994 Hom.: 1464 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.0946

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.124

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

GnomAD4 genome AF: 0.125 AC: 19009 AN: 152112 Hom.: 1471 Cov.: 32 AF XY: 0.123 AC XY: 9131 AN XY: 74368

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.0938

Gnomad4 ASJ AF: 0.0946

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.123

Alfa AF: 0.108 Hom.: 1242

Bravo AF: 0.130

Asia WGS AF: 0.0230 AC: 79 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	0.025
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs2780900; hg19: chr1-65318514;