rs149683525

Variant names:

• chr9-5055741-A-G
• rs149683525
• NM_004972.4:c.1009A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-5055741-A-G
• chr9-5055741-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004972.4(JAK2):​c.1009A>G​(p.Asn337Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,610,998 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: JAK2 NM_004972.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 1.72
• 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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077201426).
• BP6: Variant 9-5055741-A-G is Benign according to our data. Variant chr9-5055741-A-G is described in ClinVar as Benign. ClinVar VariationId is 134562.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0012 (182/152128) while in subpopulation AFR AF = 0.00404 (168/41558). AF 95% confidence interval is 0.00354. There are 2 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 182 AD gene.

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.1009A>G	p.Asn337Asp	missense	Exon 8 of 25	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.1009A>G	p.Asn337Asp	missense	Exon 8 of 25	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.1009A>G	p.Asn337Asp	missense	Exon 7 of 24	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.1009A>G	p.Asn337Asp	missense	Exon 8 of 25	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.1009A>G	p.Asn337Asp	missense	Exon 8 of 25	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.1009A>G	p.Asn337Asp	missense	Exon 8 of 25	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152010 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000335 AC: 84 AN: 250390 AF XY: 0.000192

Gnomad AFR exome AF: 0.00464

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000133 AC: 194 AN: 1458870 Hom.: 0 Cov.: 29 AF XY: 0.000102 AC XY: 74 AN XY: 725824

African (AFR) AF: 0.00440 AC: 147 AN: 33374

American (AMR) AF: 0.000224 AC: 10 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000901 AC: 10 AN: 1109928

Other (OTH) AF: 0.000432 AC: 26 AN: 60234

GnomAD4 genome AF: 0.00120 AC: 182 AN: 152128 Hom.: 2 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74368

African (AFR) AF: 0.00404 AC: 168 AN: 41558

American (AMR) AF: 0.000785 AC: 12 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67870

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000870 Hom.: 0

Bravo AF: 0.00149

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.00202 AC: 7 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	JAK2-related disorder (1)
-	-	1	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.11
Sift	Benign	0.66	T
Sift4G	Benign	0.62	T
Polyphen		0.072	B
Vest4		0.20
MVP		0.60
MPC		0.21
ClinPred		0.011	T
GERP RS		4.6
Varity_R		0.082
gMVP		0.38
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149683525; hg19: chr9-5055741;