9-5003338-G-A

Variant names:

• chr9-5003338-G-A
• rs4372063
• NM_004972.4:c.-26+17316G>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.-26+17316G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.671 in 151,776 control chromosomes in the GnomAD database, including 35,718 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 0.67 (35718 hom., cov: 31)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 12 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4	c.-26+17316G>A		intron_variant	Intron 2 of 24	ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.-26+17316G>A		intron_variant	Intron 2 of 24	1	NM_004972.4	ENSP00000371067.4
JAK2	ENST00000636127.1	c.-26+17316G>A		intron_variant	Intron 2 of 15	5		ENSP00000489812.1
JAK2	ENST00000476574.5	c.-26+17316G>A		intron_variant	Intron 2 of 2	3		ENSP00000490624.1

Frequencies

GnomAD3 genomes AF: 0.671 AC: 101792 AN: 151658 Hom.: 35668 Cov.: 31

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.529

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.654

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.671 AC: 101899 AN: 151776 Hom.: 35718 Cov.: 31 AF XY: 0.671 AC XY: 49742 AN XY: 74152

African (AFR) AF: 0.891 AC: 36983 AN: 41518

American (AMR) AF: 0.607 AC: 9273 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2360 AN: 3466

East Asian (EAS) AF: 0.529 AC: 2731 AN: 5160

South Asian (SAS) AF: 0.591 AC: 2848 AN: 4816

European-Finnish (FIN) AF: 0.651 AC: 6859 AN: 10536

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.572 AC: 38725 AN: 67704

Other (OTH) AF: 0.656 AC: 1380 AN: 2104

Alfa AF: 0.607 Hom.: 89406

Bravo AF: 0.675

Asia WGS AF: 0.635 AC: 2197 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.19
DANN	Benign	0.52
PhyloP100		-1.5
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: rs4372063; hg19: chr9-5003338; COSMIC: COSV67666193;