NM_004972.4:c.3060-15610A>G

Variant names:

• chr9-5107394-A-G
• rs1328918
• NM_004972.4:c.3060-15610A>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.3060-15610A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 151,912 control chromosomes in the GnomAD database, including 32,984 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 0.64 (32984 hom., cov: 31)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109
• Publications: 9 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]

MTND3P14 (HGNC:52074):

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=-0.54).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 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.3060-15610A>G		intron	N/A	NP_004963.1
	JAK2	NM_001322194.2		c.3060-15610A>G		intron	N/A	NP_001309123.1
	JAK2	NM_001322195.2		c.3060-15610A>G		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.3060-15610A>G		intron	N/A	ENSP00000371067.4

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96827 AN: 151794 Hom.: 32926 Cov.: 31

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.617

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

GnomAD4 genome AF: 0.638 AC: 96940 AN: 151912 Hom.: 32984 Cov.: 31 AF XY: 0.640 AC XY: 47495 AN XY: 74238

African (AFR) AF: 0.886 AC: 36696 AN: 41406

American (AMR) AF: 0.610 AC: 9315 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2076 AN: 3466

East Asian (EAS) AF: 0.557 AC: 2879 AN: 5168

South Asian (SAS) AF: 0.586 AC: 2813 AN: 4802

European-Finnish (FIN) AF: 0.605 AC: 6379 AN: 10550

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.512 AC: 34786 AN: 67942

Other (OTH) AF: 0.619 AC: 1306 AN: 2110

Alfa AF: 0.595 Hom.: 3454

Bravo AF: 0.650

Asia WGS AF: 0.632 AC: 2195 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.3
DANN	Benign	0.46
PhyloP100		0.11
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: rs1328918; hg19: chr9-5107394;