NM_004972.4:c.-108-61A>G

Variant names:

• chr9-4985879-A-G
• rs2274471
• NM_004972.4:c.-108-61A>G

Variant summary

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

The NM_004972.4(JAK2):​c.-108-61A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 152,786 control chromosomes in the GnomAD database, including 3,647 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 (3623 hom., cov: 32)
  • Exomes 𝑓: 0.30 (24 hom.)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.476
• Publications: 33 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4	c.-108-61A>G		intron_variant	Intron 1 of 24	ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.-108-61A>G		intron_variant	Intron 1 of 24	1	NM_004972.4	ENSP00000371067.4
JAK2	ENST00000636127.1	c.-108-61A>G		intron_variant	Intron 1 of 15	5		ENSP00000489812.1
JAK2	ENST00000476574.5	c.-108-61A>G		intron_variant	Intron 1 of 2	3		ENSP00000490624.1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32325 AN: 152110 Hom.: 3625 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.297 AC: 165 AN: 556 Hom.: 24 AF XY: 0.318 AC XY: 105 AN XY: 330

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.333 AC: 46 AN: 138

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.283 AC: 112 AN: 396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.417 AC: 5 AN: 12

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

GnomAD4 genome AF: 0.212 AC: 32330 AN: 152230 Hom.: 3623 Cov.: 32 AF XY: 0.212 AC XY: 15774 AN XY: 74426

African (AFR) AF: 0.146 AC: 6072 AN: 41550

American (AMR) AF: 0.226 AC: 3455 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1160 AN: 3470

East Asian (EAS) AF: 0.169 AC: 878 AN: 5184

South Asian (SAS) AF: 0.158 AC: 763 AN: 4826

European-Finnish (FIN) AF: 0.245 AC: 2594 AN: 10588

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16507 AN: 67996

Other (OTH) AF: 0.250 AC: 526 AN: 2108

Alfa AF: 0.235 Hom.: 13018

Bravo AF: 0.210

Asia WGS AF: 0.167 AC: 582 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.44
PhyloP100		-0.48
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: rs2274471; hg19: chr9-4985879; COSMIC: COSV67651786;