chr9-5073770-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5PP3PP5_Very_Strong

The NM_004972.4(JAK2):c.1849G>T(p.Val617Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,605,918 control chromosomes in the GnomAD database, including 17 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V617I) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00036 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 16 hom. )

Consequence

JAK2
NM_004972.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26O:2

Conservation

PhyloP100: 9.55

Publications

2151 publications found

Variant links:

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]

JAK2 links:

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]

INSL6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-5073770-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 29763.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.809

PP5

Variant 9-5073770-G-T is Pathogenic according to our data. Variant chr9-5073770-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
JAK2	NM_004972.4	MANE Select	c.1849G>T	p.Val617Phe	missense	Exon 14 of 25	NP_004963.1
JAK2	NM_001322194.2		c.1849G>T	p.Val617Phe	missense	Exon 14 of 25	NP_001309123.1
JAK2	NM_001322195.2		c.1849G>T	p.Val617Phe	missense	Exon 13 of 24	NP_001309124.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
JAK2	ENST00000381652.4	TSL:1 MANE Select	c.1849G>T	p.Val617Phe	missense	Exon 14 of 25	ENSP00000371067.4
JAK2	ENST00000870320.1		c.1849G>T	p.Val617Phe	missense	Exon 14 of 25	ENSP00000540379.1
JAK2	ENST00000870321.1		c.1849G>T	p.Val617Phe	missense	Exon 14 of 25	ENSP00000540380.1

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000352

AC:

AN:

250262

AF XY:

0.000333

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.000597

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000561

Gnomad NFE exome

AF:

0.000397

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000286

AC:

416

AN:

1454008

Hom.:

Cov.:

AF XY:

0.000343

AC XY:

248

AN XY:

723690

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33282

American (AMR)

AF:

0.000157

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.000730

AC:

AN:

26024

East Asian (EAS)

AF:

0.000101

AC:

AN:

39580

South Asian (SAS)

AF:

0.000279

AC:

AN:

85974

European-Finnish (FIN)

AF:

0.000302

AC:

AN:

52968

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000295

AC:

326

AN:

1105638

Other (OTH)

AF:

0.000216

AC:

AN:

60134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000362

AC:

AN:

151910

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74238

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000363

AC:

AN:

41374

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.000866

AC:

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5194

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000442

AC:

AN:

67902

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000141331), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.383

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000348

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000692

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

Acquired polycythemia vera (6)

Primary myelofibrosis (3)

Primary myelofibrosis;C0023467:Acute myeloid leukemia;C0032463:Acquired polycythemia vera;C0856761:Budd-Chiari syndrome;C3281125:Thrombocythemia 3;C4551637:Primary familial polycythemia due to EPO receptor mutation (2)

Thrombocythemia 3 (2)

Acute myeloid leukemia (1)

JAK2-related disorder (1)

Myeloproliferative disorder (1)

Polycythemia (1)

Primary myelofibrosis;C0038002:Splenomegaly (1)

Budd-Chiari syndrome, susceptibility to, somatic (1)

Primary familial polycythemia due to EPO receptor mutation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.1

PhyloP100

9.5

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.89

MVP

0.97

MPC

0.84

ClinPred

0.92

GERP RS

5.5

Varity_R

0.88

gMVP

0.72

Mutation Taster

=24/76

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over