1-64835422-G-A
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_002227.4(JAK1):c.3343C>T(p.Pro1115Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,605,708 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1115L) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 1 hom. )
Consequence
JAK1
NM_002227.4 missense
NM_002227.4 missense
Scores
4
10
5
Clinical Significance
Conservation
PhyloP100: 6.19
Genes affected
JAK1 (HGNC:6190): (Janus kinase 1) This gene encodes a membrane protein that is a member of a class of protein-tyrosine kinases (PTK) characterized by the presence of a second phosphotransferase-related domain immediately N-terminal to the PTK domain. The encoded kinase phosphorylates STAT proteins (signal transducers and activators of transcription) and plays a key role in interferon-alpha/beta, interferon-gamma, and cytokine signal transduction. This gene plays a crucial role in effecting the expression of genes that mediate inflammation, epithelial remodeling, and metastatic cancer progression. This gene is a key component of the interleukin-6 (IL-6)/JAK1/STAT3 immune and inflammation response and is a therapeutic target for alleviating cytokine storms. The kinase activity of this gene is directly inhibited by the suppressor of cytokine signalling 1 (SOCS1) protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2020]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP2
Missense variant where missense usually causes diseases, JAK1
BS2
High AC in GnomAdExome4 at 17 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JAK1 | NM_002227.4 | c.3343C>T | p.Pro1115Ser | missense_variant | 24/25 | ENST00000342505.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAK1 | ENST00000342505.5 | c.3343C>T | p.Pro1115Ser | missense_variant | 24/25 | 5 | NM_002227.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152180Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000163 AC: 4AN: 244952Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133158
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GnomAD4 exome AF: 0.0000117 AC: 17AN: 1453528Hom.: 1 Cov.: 29 AF XY: 0.0000207 AC XY: 15AN XY: 723550
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 01, 2022 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1115 of the JAK1 protein (p.Pro1115Ser). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 1509416). This variant has not been reported in the literature in individuals affected with JAK1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at