rs10119004

Variant names:

• chr9-5071049-G-A
• rs10119004
• NM_004972.4:c.1641+997G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004972.4(JAK2):​c.1641+997G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 152,060 control chromosomes in the GnomAD database, including 32,061 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (32061 hom., cov: 31)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.918
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4	c.1641+997G>A		intron_variant	Intron 12 of 24	ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.1641+997G>A		intron_variant	Intron 12 of 24	1	NM_004972.4	ENSP00000371067.4
JAK2	ENST00000636127.1	c.1641+997G>A		intron_variant	Intron 12 of 15	5		ENSP00000489812.1

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95371 AN: 151940 Hom.: 32010 Cov.: 31

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.542

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.601

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.628 AC: 95480 AN: 152060 Hom.: 32061 Cov.: 31 AF XY: 0.626 AC XY: 46541 AN XY: 74314

African (AFR) AF: 0.883 AC: 36654 AN: 41520

American (AMR) AF: 0.551 AC: 8400 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2020 AN: 3468

East Asian (EAS) AF: 0.442 AC: 2286 AN: 5176

South Asian (SAS) AF: 0.521 AC: 2509 AN: 4818

European-Finnish (FIN) AF: 0.579 AC: 6108 AN: 10552

Middle Eastern (MID) AF: 0.514 AC: 150 AN: 292

European-Non Finnish (NFE) AF: 0.522 AC: 35449 AN: 67962

Other (OTH) AF: 0.603 AC: 1269 AN: 2106

Alfa AF: 0.575 Hom.: 11122

Bravo AF: 0.634

Asia WGS AF: 0.548 AC: 1904 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.93
DANN	Benign	0.65
PhyloP100		0.92
Mutation Taster		=100/0	polymorphism (auto)

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: rs10119004; hg19: chr9-5071049;