chr9-5126715-A-G

Position:

chr9-5126715-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004972.4(JAK2):c.3323A>G(p.Asn1108Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,610,826 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1108K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 8 hom. )

Consequence

JAK2
NM_004972.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 3.47

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009206653).

BP6

Variant 9-5126715-A-G is Benign according to our data. Variant chr9-5126715-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134557.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr9-5126715-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00207 (314/151868) while in subpopulation NFE AF= 0.00337 (228/67660). AF 95% confidence interval is 0.00301. There are 0 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 314 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK2	NM_004972.4 linkuse as main transcript	c.3323A>G	p.Asn1108Ser	missense_variant	25/25	ENST00000381652.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
JAK2	ENST00000381652.4 linkuse as main transcript	c.3323A>G	p.Asn1108Ser	missense_variant	25/25	1	NM_004972.4	P1
INSL6	ENST00000649639.1 linkuse as main transcript	c.*11-2204T>C		intron_variant
JAK2	ENST00000487310.1 linkuse as main transcript	n.514A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.00207

AC:

314

AN:

151750

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00243

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00337

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00198

AC:

494

AN:

250064

Hom.:

AF XY:

0.00206

AC XY:

279

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.000741

Gnomad AMR exome

AF:

0.00288

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000393

Gnomad FIN exome

AF:

0.000557

Gnomad NFE exome

AF:

0.00297

Gnomad OTH exome

AF:

0.00394

GnomAD4 exome

AF:

0.00341

AC:

4968

AN:

1458958

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

2389

AN XY:

725822

show subpopulations

Gnomad4 AFR exome

AF:

0.000719

Gnomad4 AMR exome

AF:

0.00312

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000395

Gnomad4 FIN exome

AF:

0.000562

Gnomad4 NFE exome

AF:

0.00409

Gnomad4 OTH exome

AF:

0.00332

GnomAD4 genome

AF:

0.00207

AC:

314

AN:

151868

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00243

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.00337

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00320

Hom.:

Bravo

AF:

0.00246

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00191

AC:

232

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00317

EpiControl

AF:

0.00398

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	JAK2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 27, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Thrombocythemia 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Feb 10, 2020

This JAK2 variant (rs142269166) is present in a large population datasets (gnomAD: 552/281382 total alleles; 0.1962%; no homozygotes), but believed to be overrepresented in patients with myeloproliferative neoplasms. Bioinformatic tools queried predict that the substitution would be tolerated, but these algorithms have low specificity, especially for predicting gain of function variants. Due to lack of segregation and functional data, we consider the clinical significance of c.3323A>G to be uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.045

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.84

M_CAP

Benign

0.028

MetaRNN

Benign

0.0092

MetaSVM

Benign

-0.57

MutationAssessor

Benign

-0.43

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

0.34

REVEL

Uncertain

0.35

Sift

Benign

0.43

Sift4G

Benign

0.51

Polyphen

0.0030

Vest4

0.10

MVP

0.64

MPC

0.14

ClinPred

0.0097

GERP RS

5.3

Varity_R

0.19

gMVP

0.29

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over