chr9-5097281-A-C

Variant names:

• chr9-5097281-A-C
• rs7847294
• NM_004972.4:c.3059+6370A>C

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+6370A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 152,038 control chromosomes in the GnomAD database, including 33,424 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 0.64 (33418 hom., cov: 31)
  • Exomes 𝑓: 0.59 (6 hom.)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13
• 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]

MTCO1P11 (HGNC:52013): (MT-CO1 pseudogene 11)

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=-0.62).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 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.3059+6370A>C		intron	N/A	NP_004963.1
	JAK2	NM_001322194.2		c.3059+6370A>C		intron	N/A	NP_001309123.1
	JAK2	NM_001322195.2		c.3059+6370A>C		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.3059+6370A>C		intron	N/A	ENSP00000371067.4
	MTCO1P11	ENST00000429111.1	TSL:6	n.616A>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97499 AN: 151886 Hom.: 33355 Cov.: 31

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.620

GnomAD4 exome AF: 0.588 AC: 20 AN: 34 Hom.: 6 Cov.: 0 AF XY: 0.583 AC XY: 14 AN XY: 24

African (AFR) AF: 1.00 AC: 2 AN: 2

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) AF: 0.500 AC: 2 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.577 AC: 15 AN: 26

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.642 AC: 97616 AN: 152004 Hom.: 33418 Cov.: 31 AF XY: 0.644 AC XY: 47843 AN XY: 74296

African (AFR) AF: 0.893 AC: 37066 AN: 41502

American (AMR) AF: 0.612 AC: 9337 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 2059 AN: 3470

East Asian (EAS) AF: 0.591 AC: 3039 AN: 5138

South Asian (SAS) AF: 0.589 AC: 2834 AN: 4814

European-Finnish (FIN) AF: 0.609 AC: 6433 AN: 10558

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.513 AC: 34859 AN: 67942

Other (OTH) AF: 0.622 AC: 1314 AN: 2112

Alfa AF: 0.600 Hom.: 9254

Bravo AF: 0.653

Asia WGS AF: 0.650 AC: 2258 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.8
DANN	Benign	0.55
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs7847294; hg19: chr9-5097281;