NM_004972.4:c.3060-8481A>C

Variant names:

• chr9-5114523-A-C
• rs3780381
• NM_004972.4:c.3060-8481A>C

Variant summary

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

The NM_004972.4(JAK2):​c.3060-8481A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 464,646 control chromosomes in the GnomAD database, including 18,148 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 0.25 (5045 hom., cov: 32)
  • Exomes 𝑓: 0.29 (13103 hom.)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• Publications: 17 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]

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

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.288 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	NM_004972.4	MANE Select	c.3060-8481A>C		intron	N/A	NP_004963.1
	JAK2	NM_001322194.2		c.3060-8481A>C		intron	N/A	NP_001309123.1
	JAK2	NM_001322195.2		c.3060-8481A>C		intron	N/A	NP_001309124.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	ENST00000381652.4	TSL:1 MANE Select	c.3060-8481A>C		intron	N/A	ENSP00000371067.4
	IGHEP2	ENST00000519308.1	TSL:6	n.975A>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38034 AN: 151742 Hom.: 5050 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.286 AC: 89329 AN: 312786 Hom.: 13103 Cov.: 0 AF XY: 0.287 AC XY: 49838 AN XY: 173668

African (AFR) AF: 0.166 AC: 1447 AN: 8724

American (AMR) AF: 0.297 AC: 6850 AN: 23056

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 2405 AN: 9438

East Asian (EAS) AF: 0.265 AC: 3455 AN: 13048

South Asian (SAS) AF: 0.289 AC: 14759 AN: 51052

European-Finnish (FIN) AF: 0.341 AC: 7126 AN: 20900

Middle Eastern (MID) AF: 0.289 AC: 355 AN: 1230

European-Non Finnish (NFE) AF: 0.286 AC: 48460 AN: 169316

Other (OTH) AF: 0.279 AC: 4472 AN: 16022

GnomAD4 genome AF: 0.250 AC: 38040 AN: 151860 Hom.: 5045 Cov.: 32 AF XY: 0.254 AC XY: 18828 AN XY: 74210

African (AFR) AF: 0.163 AC: 6733 AN: 41420

American (AMR) AF: 0.295 AC: 4508 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 883 AN: 3464

East Asian (EAS) AF: 0.255 AC: 1312 AN: 5148

South Asian (SAS) AF: 0.296 AC: 1426 AN: 4814

European-Finnish (FIN) AF: 0.332 AC: 3501 AN: 10544

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18824 AN: 67888

Other (OTH) AF: 0.259 AC: 548 AN: 2112

Alfa AF: 0.274 Hom.: 4033

Bravo AF: 0.241

Asia WGS AF: 0.259 AC: 898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.1
DANN	Benign	0.57
PhyloP100		2.0
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: rs3780381; hg19: chr9-5114523; COSMIC: COSV67594847; COSMIC: COSV67594847;