9-5126715-A-G

Variant names:

• chr9-5126715-A-G
• rs142269166
• NM_004972.4:c.3323A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 14/22 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3 O:1
• Conservation: PhyloP100: 3.47
• Publications: 33 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 -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: {Uncertain_significance=3, Benign=1, other=1, Likely_benign=2}.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 314 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4	c.3323A>G	p.Asn1108Ser	missense_variant	Exon 25 of 25	ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.3323A>G	p.Asn1108Ser	missense_variant	Exon 25 of 25	1	NM_004972.4	ENSP00000371067.4
JAK2	ENST00000487310.1	n.514A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
INSL6	ENST00000649639.1	c.*11-2204T>C		intron_variant	Intron 3 of 3			ENSP00000497955.1

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 314 AN: 151750 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00198 AC: 494 AN: 250064 AF XY: 0.00206

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 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.: 8 Cov.: 29 AF XY: 0.00329 AC XY: 2389 AN XY: 725822

African (AFR) AF: 0.000719 AC: 24 AN: 33376

American (AMR) AF: 0.00312 AC: 139 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.000395 AC: 34 AN: 86108

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53338

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.00409 AC: 4535 AN: 1109884

Other (OTH) AF: 0.00332 AC: 200 AN: 60268

GnomAD4 genome AF: 0.00207 AC: 314 AN: 151868 Hom.: 0 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74268

African (AFR) AF: 0.000794 AC: 33 AN: 41564

American (AMR) AF: 0.00243 AC: 37 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00337 AC: 228 AN: 67660

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00305 Hom.: 1

Bravo AF: 0.00246

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00191 AC: 232

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00317

EpiControl AF: 0.00398

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

JAK2: BP4, BS1 -

Jul 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

May 27, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thrombocythemia 3 Uncertain:1

Feb 10, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.43	N
PhyloP100		3.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.34	N
REVEL	Uncertain	0.35
Sift	Benign	0.43	T
Sift4G	Benign	0.51	T
Polyphen		0.0030	B
Vest4		0.10
MVP		0.64
MPC		0.14
ClinPred		0.0097	T
GERP RS		5.3
Varity_R		0.19
gMVP		0.29
Mutation Taster		=74/26	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: rs142269166; hg19: chr9-5126715; COSMIC: COSV67611201;