rs3780378

Variant names:

• chr9-5112288-C-T
• rs3780378
• NM_004972.4:c.3060-10716C>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.3060-10716C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 257,364 control chromosomes in the GnomAD database, including 33,071 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 0.51 (19811 hom., cov: 33)
  • Exomes 𝑓: 0.49 (13260 hom.)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215
• Publications: 19 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]

TCF3P1 (HGNC:49742): (transcription factor 3 pseudogene 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.519 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.3060-10716C>T		intron	N/A	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.3060-10716C>T		intron	N/A	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.3060-10716C>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.3060-10716C>T		intron	N/A	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.3060-10716C>T		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.3060-10716C>T		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77170 AN: 151896 Hom.: 19800 Cov.: 33

Gnomad AFR AF: 0.482

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.509

GnomAD4 exome AF: 0.491 AC: 51770 AN: 105350 Hom.: 13260 Cov.: 0 AF XY: 0.496 AC XY: 28510 AN XY: 57486

African (AFR) AF: 0.451 AC: 860 AN: 1908

American (AMR) AF: 0.460 AC: 1965 AN: 4272

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1296 AN: 2324

East Asian (EAS) AF: 0.468 AC: 1723 AN: 3678

South Asian (SAS) AF: 0.504 AC: 9126 AN: 18092

European-Finnish (FIN) AF: 0.573 AC: 3404 AN: 5944

Middle Eastern (MID) AF: 0.522 AC: 242 AN: 464

European-Non Finnish (NFE) AF: 0.481 AC: 30172 AN: 62694

Other (OTH) AF: 0.499 AC: 2982 AN: 5974

GnomAD4 genome AF: 0.508 AC: 77212 AN: 152014 Hom.: 19811 Cov.: 33 AF XY: 0.513 AC XY: 38141 AN XY: 74318

African (AFR) AF: 0.482 AC: 19983 AN: 41450

American (AMR) AF: 0.508 AC: 7763 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2033 AN: 3468

East Asian (EAS) AF: 0.520 AC: 2667 AN: 5128

South Asian (SAS) AF: 0.536 AC: 2588 AN: 4826

European-Finnish (FIN) AF: 0.600 AC: 6353 AN: 10588

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.501 AC: 34074 AN: 67950

Other (OTH) AF: 0.508 AC: 1073 AN: 2112

Alfa AF: 0.515 Hom.: 2590

Bravo AF: 0.498

Asia WGS AF: 0.532 AC: 1848 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.9
DANN	Benign	0.84
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3780378; hg19: chr9-5112288;