9-5112519-G-A

Variant names:

• chr9-5112519-G-A
• rs3780379
• NM_004972.4:c.3060-10485G>A

Variant summary

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

The NM_004972.4(JAK2):​c.3060-10485G>A variant causes a intron change. The variant allele was found at a frequency of 0.175 in 575,380 control chromosomes in the GnomAD database, including 9,628 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 0.16 (2282 hom., cov: 32)
  • Exomes 𝑓: 0.18 (7346 hom.)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.92
• Publications: 16 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]

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

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=-0.63).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.198 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.3060-10485G>A		intron	N/A	NP_004963.1
	JAK2	NM_001322194.2		c.3060-10485G>A		intron	N/A	NP_001309123.1
	JAK2	NM_001322195.2		c.3060-10485G>A		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.3060-10485G>A		intron	N/A	ENSP00000371067.4
	TCF3P1	ENST00000423021.2	TSL:6	n.1607G>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24399 AN: 151956 Hom.: 2284 Cov.: 32

Gnomad AFR AF: 0.0632

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.187

GnomAD4 exome AF: 0.180 AC: 76363 AN: 423306 Hom.: 7346 Cov.: 4 AF XY: 0.179 AC XY: 41103 AN XY: 229172

African (AFR) AF: 0.0599 AC: 616 AN: 10290

American (AMR) AF: 0.151 AC: 3263 AN: 21610

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 3227 AN: 11948

East Asian (EAS) AF: 0.169 AC: 4605 AN: 27188

South Asian (SAS) AF: 0.132 AC: 5051 AN: 38334

European-Finnish (FIN) AF: 0.219 AC: 7687 AN: 35070

Middle Eastern (MID) AF: 0.189 AC: 503 AN: 2656

European-Non Finnish (NFE) AF: 0.186 AC: 46959 AN: 252552

Other (OTH) AF: 0.188 AC: 4452 AN: 23658

GnomAD4 genome AF: 0.160 AC: 24394 AN: 152074 Hom.: 2282 Cov.: 32 AF XY: 0.162 AC XY: 12050 AN XY: 74322

African (AFR) AF: 0.0630 AC: 2614 AN: 41504

American (AMR) AF: 0.175 AC: 2678 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 961 AN: 3464

East Asian (EAS) AF: 0.208 AC: 1071 AN: 5140

South Asian (SAS) AF: 0.144 AC: 694 AN: 4810

European-Finnish (FIN) AF: 0.225 AC: 2386 AN: 10590

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

European-Non Finnish (NFE) AF: 0.195 AC: 13263 AN: 67958

Other (OTH) AF: 0.188 AC: 397 AN: 2114

Alfa AF: 0.189 Hom.: 3525

Bravo AF: 0.156

Asia WGS AF: 0.177 AC: 616 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	1.8
DANN	Benign	0.74
PhyloP100		6.9
Mutation Taster		=99/1	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: rs3780379; hg19: chr9-5112519;