9-5112519-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004972.4(JAK2):​c.3060-10485G>T variant causes a intron change. The variant allele was found at a frequency of 0.00000236 in 424,372 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.92
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).

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.3060-10485G>T		intron	N/A	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.3060-10485G>T		intron	N/A	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.3060-10485G>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.3060-10485G>T		intron	N/A	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.3060-10485G>T		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.3060-10485G>T		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000236 AC: 1 AN: 424372 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 229764

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10296

American (AMR) AF: 0.00 AC: 0 AN: 21676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11984

East Asian (EAS) AF: 0.00 AC: 0 AN: 27244

South Asian (SAS) AF: 0.00 AC: 0 AN: 38440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2666

European-Non Finnish (NFE) AF: 0.00000395 AC: 1 AN: 253206

Other (OTH) AF: 0.00 AC: 0 AN: 23700

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.6
DANN	Benign	0.75
PhyloP100		6.9

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;