9-5097544-C-T

Variant names:

• chr9-5097544-C-T
• rs3780372
• NM_004972.4:c.3059+6633C>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.3059+6633C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 151,934 control chromosomes in the GnomAD database, including 8,856 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 0.33 (8855 hom., cov: 31)
  • Exomes 𝑓: 0.40 (1 hom.)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04
• Publications: 13 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]

MTCO1P11 (HGNC:52013): (MT-CO1 pseudogene 11)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.439 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.3059+6633C>T		intron	N/A	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.3059+6633C>T		intron	N/A	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.3059+6633C>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.3059+6633C>T		intron	N/A	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.3059+6633C>T		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.3059+6633C>T		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50840 AN: 151808 Hom.: 8843 Cov.: 31

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.400 AC: 4 AN: 10 Hom.: 1 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.500 AC: 3 AN: 6

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.335 AC: 50894 AN: 151924 Hom.: 8855 Cov.: 31 AF XY: 0.336 AC XY: 24953 AN XY: 74238

African (AFR) AF: 0.445 AC: 18422 AN: 41418

American (AMR) AF: 0.325 AC: 4970 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 894 AN: 3472

East Asian (EAS) AF: 0.261 AC: 1349 AN: 5172

South Asian (SAS) AF: 0.324 AC: 1556 AN: 4804

European-Finnish (FIN) AF: 0.340 AC: 3576 AN: 10518

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19118 AN: 67960

Other (OTH) AF: 0.325 AC: 684 AN: 2106

Alfa AF: 0.290 Hom.: 5881

Bravo AF: 0.335

Asia WGS AF: 0.318 AC: 1102 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.13
DANN	Benign	0.33
PhyloP100		3.0
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: rs3780372; hg19: chr9-5097544;