chr9-5109531-C-T

Variant names:

• chr9-5109531-C-T
• rs10491652
• NM_004972.4:c.3060-13473C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004972.4(JAK2):​c.3060-13473C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,166 control chromosomes in the GnomAD database, including 2,765 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 0.11 (2765 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.03
• Publications: 4 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]

MTND5P14 (HGNC:42276): (MT-ND5 pseudogene 14)

MTND4P14 (HGNC:42201): (MT-ND4 pseudogene 14)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 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.3060-13473C>T		intron	N/A	NP_004963.1
	JAK2	NM_001322194.2		c.3060-13473C>T		intron	N/A	NP_001309123.1
	JAK2	NM_001322195.2		c.3060-13473C>T		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.3060-13473C>T		intron	N/A	ENSP00000371067.4
	JAK2	ENST00000870320.1		c.3060-13473C>T		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.3060-13473C>T		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16245 AN: 152050 Hom.: 2755 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00391

Gnomad OTH AF: 0.0733

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

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) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.107 AC: 16290 AN: 152166 Hom.: 2765 Cov.: 32 AF XY: 0.103 AC XY: 7674 AN XY: 74410

African (AFR) AF: 0.365 AC: 15109 AN: 41448

American (AMR) AF: 0.0380 AC: 582 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5186

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00391 AC: 266 AN: 68020

Other (OTH) AF: 0.0769 AC: 162 AN: 2108

Alfa AF: 0.108 Hom.: 471

Bravo AF: 0.120

Asia WGS AF: 0.0600 AC: 207 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.72
PhyloP100		-4.0
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: rs10491652; hg19: chr9-5109531;