1-64958277-T-C

Variant names:

• chr1-64958277-T-C
• rs7546545
• NM_002227.4:c.-78+8056A>G

Variant summary

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

The ENST00000342505.5(JAK1):​c.-78+8056A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 152,096 control chromosomes in the GnomAD database, including 35,558 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 0.66 (35558 hom., cov: 33)
• Consequence: JAK1 ENST00000342505.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 5 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000342505.5. 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.-78+8056A>G		intron	N/A	NP_002218.2
	JAK1	NM_001320923.2		c.-161-1260A>G		intron	N/A	NP_001307852.1
	JAK1	NM_001321852.2		c.-77-71936A>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.-78+8056A>G		intron	N/A	ENSP00000343204.4
	JAK1	ENST00000671929.2		c.-161-1260A>G		intron	N/A	ENSP00000500485.1
	JAK1	ENST00000671954.2		c.-77-71936A>G		intron	N/A	ENSP00000500841.1

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100328 AN: 151976 Hom.: 35537 Cov.: 33

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.710

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

GnomAD4 genome AF: 0.660 AC: 100382 AN: 152096 Hom.: 35558 Cov.: 33 AF XY: 0.659 AC XY: 49020 AN XY: 74350

African (AFR) AF: 0.386 AC: 16024 AN: 41480

American (AMR) AF: 0.801 AC: 12252 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 2453 AN: 3472

East Asian (EAS) AF: 0.587 AC: 3038 AN: 5174

South Asian (SAS) AF: 0.737 AC: 3554 AN: 4822

European-Finnish (FIN) AF: 0.663 AC: 7001 AN: 10554

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.788 AC: 53583 AN: 67988

Other (OTH) AF: 0.713 AC: 1504 AN: 2110

Alfa AF: 0.760 Hom.: 22365

Bravo AF: 0.659

Asia WGS AF: 0.649 AC: 2259 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.99
DANN	Benign	0.72
PhyloP100		-1.3
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: rs7546545; hg19: chr1-65423960; COSMIC: COSV61089226;