chr9-5056931-C-A

Variant names:

• chr9-5056931-C-A
• rs1536798
• NM_004972.4:c.1056+1143C>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.1056+1143C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 151,982 control chromosomes in the GnomAD database, including 29,667 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 0.60 (29667 hom., cov: 32)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.194
• Publications: 10 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 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.1056+1143C>A		intron	N/A	NP_004963.1
	JAK2	NM_001322194.2		c.1056+1143C>A		intron	N/A	NP_001309123.1
	JAK2	NM_001322195.2		c.1056+1143C>A		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.1056+1143C>A		intron	N/A	ENSP00000371067.4
	JAK2	ENST00000636127.1	TSL:5	c.1056+1143C>A		intron	N/A	ENSP00000489812.1

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91322 AN: 151862 Hom.: 29619 Cov.: 32

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.582

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

GnomAD4 genome AF: 0.602 AC: 91435 AN: 151982 Hom.: 29667 Cov.: 32 AF XY: 0.599 AC XY: 44494 AN XY: 74274

African (AFR) AF: 0.862 AC: 35778 AN: 41522

American (AMR) AF: 0.531 AC: 8108 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2010 AN: 3470

East Asian (EAS) AF: 0.369 AC: 1906 AN: 5162

South Asian (SAS) AF: 0.504 AC: 2433 AN: 4826

European-Finnish (FIN) AF: 0.545 AC: 5744 AN: 10548

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.494 AC: 33544 AN: 67878

Other (OTH) AF: 0.585 AC: 1236 AN: 2114

Alfa AF: 0.536 Hom.: 2441

Bravo AF: 0.610

Asia WGS AF: 0.503 AC: 1747 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.0
DANN	Benign	0.56
PhyloP100		0.19
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: rs1536798; hg19: chr9-5056931;