rs3780379

Positions:

• chr9-5112519-G-A

Variant summary

Our verdict is Benign. Variant got -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

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:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK2	NM_004972.4	c.3060-10485G>A		intron_variant		ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.3060-10485G>A		intron_variant		1	NM_004972.4	ENSP00000371067.4
TCF3P1	ENST00000423021.2	n.1607G>A		non_coding_transcript_exon_variant	1/1	6

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

Gnomad4 AFR exome AF: 0.0599

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.169

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.186

Gnomad4 OTH exome AF: 0.188

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

Gnomad4 AFR AF: 0.0630

Gnomad4 AMR AF: 0.175

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.208

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.225

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.188

Alfa AF: 0.195 Hom.: 2770

Bravo AF: 0.156

Asia WGS AF: 0.177 AC: 616 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.8
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs3780379; hg19: chr9-5112519;