rs3824433

Variant names:

• chr9-5113577-C-T
• rs3824433
• NM_004972.4:c.3060-9427C>T

Variant summary

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

The NM_004972.4(JAK2):​c.3060-9427C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 157,228 control chromosomes in the GnomAD database, including 10,802 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 0.36 (10585 hom., cov: 30)
  • Exomes 𝑓: 0.26 (217 hom.)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04
• Publications: 12 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]

INSL6 (HGNC:6089): (insulin like 6) The protein encoded by this gene contains a classical signature of the insulin superfamily and is significantly similar to relaxin and relaxin-like factor. This gene is preferentially expressed in testis. Its expression in testis is restricted to interstitial cells surrounding seminiferous tubules, which suggests a role in sperm development and fertilization. [provided by RefSeq, Jul 2008]

IGHEP2 (HGNC:5524): (immunoglobulin heavy constant epsilon P2 (pseudogene))

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004972.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	NM_004972.4	MANE Select	c.3060-9427C>T		intron	N/A	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.3060-9427C>T		intron	N/A	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.3060-9427C>T		intron	N/A	NP_001309124.1	O60674

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	ENST00000381652.4	TSL:1 MANE Select	c.3060-9427C>T		intron	N/A	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.3060-9427C>T		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.3060-9427C>T		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54298 AN: 151482 Hom.: 10574 Cov.: 30

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.258 AC: 1454 AN: 5628 Hom.: 217 Cov.: 0 AF XY: 0.263 AC XY: 802 AN XY: 3052

African (AFR) AF: 0.500 AC: 25 AN: 50

American (AMR) AF: 0.282 AC: 22 AN: 78

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 13 AN: 56

East Asian (EAS) AF: 0.125 AC: 9 AN: 72

South Asian (SAS) AF: 0.266 AC: 220 AN: 828

European-Finnish (FIN) AF: 0.275 AC: 564 AN: 2054

Middle Eastern (MID) AF: 0.273 AC: 6 AN: 22

European-Non Finnish (NFE) AF: 0.248 AC: 540 AN: 2178

Other (OTH) AF: 0.190 AC: 55 AN: 290

GnomAD4 genome AF: 0.359 AC: 54350 AN: 151600 Hom.: 10585 Cov.: 30 AF XY: 0.358 AC XY: 26539 AN XY: 74106

African (AFR) AF: 0.530 AC: 21851 AN: 41218

American (AMR) AF: 0.335 AC: 5102 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 897 AN: 3468

East Asian (EAS) AF: 0.260 AC: 1340 AN: 5146

South Asian (SAS) AF: 0.322 AC: 1547 AN: 4802

European-Finnish (FIN) AF: 0.334 AC: 3519 AN: 10538

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.281 AC: 19061 AN: 67880

Other (OTH) AF: 0.335 AC: 705 AN: 2102

Alfa AF: 0.310 Hom.: 22777

Bravo AF: 0.362

Asia WGS AF: 0.319 AC: 1106 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.4
DANN	Benign	0.46
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs3824433; hg19: chr9-5113577; COSMIC: COSV67572034; COSMIC: COSV67572034;