9-4984549-G-T

Variant names:

• chr9-4984549-G-T
• rs1887429
• NR_169763.1:n.160G>T

Variant summary

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

The NR_169763.1(JAK2):​n.160G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 152,268 control chromosomes in the GnomAD database, including 11,330 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 0.35 (11326 hom., cov: 33)
  • Exomes 𝑓: 0.21 (4 hom.)
• Consequence: JAK2 NR_169763.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.852
• Publications: 24 publications found

Genes affected

JAK2 (HGNC:6192): (Janus kinase 2) This gene encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signalling. The primary isoform of this protein has an N-terminal FERM domain that is required for erythropoietin receptor association, an SH2 domain that binds STAT transcription factors, a pseudokinase domain and a C-terminal tyrosine kinase domain. Cytokine binding induces autophosphorylation and activation of this kinase. This kinase then recruits and phosphorylates signal transducer and activator of transcription (STAT) proteins. Growth factors like TGF-beta 1 also induce phosphorylation and activation of this kinase and translocation of downstream STAT proteins to the nucleus where they influence gene transcription. Mutations in this gene are associated with numerous inflammatory diseases and malignancies. This gene is a downstream target of the pleiotropic cytokine IL6 that is produced by B cells, T cells, dendritic cells and macrophages to produce an immune response or inflammation. Disregulation of the IL6/JAK2/STAT3 signalling pathways produces increased cellular proliferation and myeloproliferative neoplasms of hematopoietic stem cells. A nonsynonymous mutation in the pseudokinase domain of this gene disrupts the domains inhibitory effect and results in constitutive tyrosine phosphorylation activity and hypersensitivity to cytokine signalling. This gene and the IL6/JAK2/STAT3 signalling pathway is a therapeutic target for the treatment of excessive inflammatory responses to viral infections. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]

JAK2 Gene-Disease associations (from GenCC):

• thrombocythemia 3

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial thrombocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NR_169763.1	n.160G>T		non_coding_transcript_exon_variant	Exon 1 of 25
JAK2	NR_169764.1	n.160G>T		non_coding_transcript_exon_variant	Exon 1 of 24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000636127.1	c.-325G>T		5_prime_UTR_variant	Exon 1 of 16	5		ENSP00000489812.1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53632 AN: 151986 Hom.: 11305 Cov.: 33

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.337

GnomAD4 exome AF: 0.213 AC: 35 AN: 164 Hom.: 4 Cov.: 0 AF XY: 0.232 AC XY: 26 AN XY: 112

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.125 AC: 1 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.500 AC: 2 AN: 4

European-Non Finnish (NFE) AF: 0.220 AC: 29 AN: 132

Other (OTH) AF: 0.167 AC: 1 AN: 6

GnomAD4 genome AF: 0.353 AC: 53707 AN: 152104 Hom.: 11326 Cov.: 33 AF XY: 0.349 AC XY: 25933 AN XY: 74358

African (AFR) AF: 0.590 AC: 24473 AN: 41466

American (AMR) AF: 0.286 AC: 4378 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1330 AN: 3470

East Asian (EAS) AF: 0.168 AC: 869 AN: 5162

South Asian (SAS) AF: 0.224 AC: 1080 AN: 4828

European-Finnish (FIN) AF: 0.247 AC: 2613 AN: 10582

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17923 AN: 67982

Other (OTH) AF: 0.338 AC: 714 AN: 2114

Alfa AF: 0.286 Hom.: 7725

Bravo AF: 0.366

Asia WGS AF: 0.248 AC: 862 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.94
DANN	Benign	0.47
PhyloP100		-0.85
PromoterAI		0.025	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1887429; hg19: chr9-4984549; COSMIC: COSV67666129;