rs3824432

Variant names:

• chr9-5091675-G-A
• rs3824432
• NM_004972.4:c.3059+764G>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.3059+764G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 151,942 control chromosomes in the GnomAD database, including 5,734 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 0.27 (5734 hom., cov: 31)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.964
• Publications: 7 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]

MTND5P36 (HGNC:51955):

MTND6P5 (HGNC:39468): (MT-ND6 pseudogene 5)

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 (AFR) allele frequency at 95% confidence interval = 0.365 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+764G>A		intron	N/A	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.3059+764G>A		intron	N/A	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.3059+764G>A		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+764G>A		intron	N/A	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.3059+764G>A		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.3059+764G>A		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40350 AN: 151818 Hom.: 5721 Cov.: 31

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.250 AC: 2 AN: 8 Hom.: 0 AF XY: 0.250 AC XY: 2 AN XY: 8

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 2 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.266 AC: 40399 AN: 151934 Hom.: 5734 Cov.: 31 AF XY: 0.264 AC XY: 19635 AN XY: 74264

African (AFR) AF: 0.370 AC: 15307 AN: 41384

American (AMR) AF: 0.227 AC: 3463 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1145 AN: 3472

East Asian (EAS) AF: 0.219 AC: 1132 AN: 5180

South Asian (SAS) AF: 0.188 AC: 905 AN: 4810

European-Finnish (FIN) AF: 0.232 AC: 2447 AN: 10554

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.222 AC: 15075 AN: 67966

Other (OTH) AF: 0.269 AC: 569 AN: 2112

Alfa AF: 0.244 Hom.: 1779

Bravo AF: 0.273

Asia WGS AF: 0.222 AC: 773 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	0.88
DANN	Benign	0.51
PhyloP100		-0.96
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: rs3824432; hg19: chr9-5091675;