chr9-5072541-G-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS1_SupportingBS2_Supporting
The NM_004972.4(JAK2):c.1691G>T(p.Arg564Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000659 in 1,608,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004972.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
JAK2 | ENST00000381652.4 | c.1691G>T | p.Arg564Leu | missense_variant | Exon 13 of 25 | 1 | NM_004972.4 | ENSP00000371067.4 | ||
JAK2 | ENST00000636127.1 | c.1691G>T | p.Arg564Leu | missense_variant | Exon 13 of 16 | 5 | ENSP00000489812.1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152170Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000641 AC: 16AN: 249532Hom.: 0 AF XY: 0.0000890 AC XY: 12AN XY: 134904
GnomAD4 exome AF: 0.0000687 AC: 100AN: 1455928Hom.: 0 Cov.: 29 AF XY: 0.0000760 AC XY: 55AN XY: 724030
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152170Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74328
ClinVar
Submissions by phenotype
not provided Uncertain:3
The JAK2 p.Arg564Leu variant was identified in the literature in 3 of 20,000 samples from patients with suspected Myeloproliferative Neoplasias (Ma_2009_PMID:19074595). The variant was also identified in dbSNP (ID: rs368927897) and ClinVar (classified as likely pathogenic by Database of Curated Mutations (DoCM) for Myeloproliferative disorder as a somatic mutation). The variant was identified in control databases in 17 of 280934 chromosomes at a frequency of 0.00006051 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 3 of 10314 chromosomes (freq: 0.000291), European (non-Finnish) in 12 of 128456 chromosomes (freq: 0.000093) and South Asian in 2 of 30264 chromosomes (freq: 0.000066), but was not observed in the African, Latino, East Asian, European (Finnish), or Other populations. The p.Arg564 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Identified in blood and/or bone marrow samples from individuals with myeloproliferative neoplasms (PMID: 19074595, 30811597, 36810551); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24381227, 36810551, 19744331, 19074595, 30811597) -
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 564 of the JAK2 protein (p.Arg564Leu). This variant is present in population databases (rs368927897, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with JAK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 376706). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt JAK2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
JAK2-related disorder Uncertain:1
The JAK2 c.1691G>T variant is predicted to result in the amino acid substitution p.Arg564Leu. This variant has been reported in patients with chronic myeloproliferative neoplasias (Ma et al. 2009. PubMed ID: 19074595). In addition, another variant (c.1691G>A) affecting the same amino acid (p.Arg564Gln) has been reported in familial essential thrombocytosis (Etheridge et al. 2014. PubMed ID: 24381227). This variant is reported in 0.029% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at