chr9-5126343-G-A

Variant names:

• chr9-5126343-G-A
• rs41316003
• NM_004972.4:c.3188G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004972.4(JAK2):​c.3188G>A​(p.Arg1063His) variant causes a missense change. The variant allele was found at a frequency of 0.00539 in 1,600,698 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (41 hom.)
• Consequence: JAK2 NM_004972.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 4.23
• Publications: 64 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01177606).
• BP6: Variant 9-5126343-G-A is Benign according to our data. Variant chr9-5126343-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00489 (742/151770) while in subpopulation NFE AF = 0.00757 (512/67608). AF 95% confidence interval is 0.00703. There are 5 homozygotes in GnomAd4. There are 342 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 742 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	NM_004972.4	MANE Select	c.3188G>A	p.Arg1063His	missense	Exon 24 of 25	NP_004963.1
	JAK2	NM_001322194.2		c.3188G>A	p.Arg1063His	missense	Exon 24 of 25	NP_001309123.1
	JAK2	NM_001322195.2		c.3188G>A	p.Arg1063His	missense	Exon 23 of 24	NP_001309124.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	ENST00000381652.4	TSL:1 MANE Select	c.3188G>A	p.Arg1063His	missense	Exon 24 of 25	ENSP00000371067.4
	JAK2	ENST00000487310.1	TSL:2	n.379G>A		non_coding_transcript_exon	Exon 1 of 2
	INSL6	ENST00000649639.1		c.*11-1832C>T		intron	N/A	ENSP00000497955.1

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 742 AN: 151652 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00329

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00757

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00437 AC: 1063 AN: 243412 AF XY: 0.00432

Gnomad AFR exome AF: 0.000886

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.000819

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.00596

Gnomad OTH exome AF: 0.00470

GnomAD4 exome AF: 0.00544 AC: 7888 AN: 1448928 Hom.: 41 Cov.: 28 AF XY: 0.00547 AC XY: 3944 AN XY: 720816

African (AFR) AF: 0.000760 AC: 25 AN: 32882

American (AMR) AF: 0.00197 AC: 85 AN: 43164

Ashkenazi Jewish (ASJ) AF: 0.000891 AC: 23 AN: 25818

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39308

South Asian (SAS) AF: 0.00249 AC: 210 AN: 84200

European-Finnish (FIN) AF: 0.0110 AC: 584 AN: 53282

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5724

European-Non Finnish (NFE) AF: 0.00603 AC: 6665 AN: 1104628

Other (OTH) AF: 0.00481 AC: 288 AN: 59922

GnomAD4 genome AF: 0.00489 AC: 742 AN: 151770 Hom.: 5 Cov.: 32 AF XY: 0.00461 AC XY: 342 AN XY: 74214

African (AFR) AF: 0.000867 AC: 36 AN: 41532

American (AMR) AF: 0.00335 AC: 51 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3460

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00757 AC: 512 AN: 67608

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00488 Hom.: 6

Bravo AF: 0.00365

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00432 AC: 525

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00644

EpiControl AF: 0.00646

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

JAK2: BS1, BS2

Jan 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32172663, 30377194, 27389715, 23670291, 31135094, 19643476, 29296762)

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

May 18, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

JAK2-related disorder Benign:1

Oct 06, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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 Benign:1

Apr 22, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	0.0072
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.93	L
PhyloP100		4.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.28
Sift	Benign	0.058	T
Sift4G	Benign	0.083	T
Polyphen		0.060	B
Vest4		0.82
MVP		0.76
MPC		0.51
ClinPred		0.018	T
GERP RS		5.1
Varity_R		0.27
gMVP		0.46
Mutation Taster		=66/34	polymorphism

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: rs41316003; hg19: chr9-5126343;