rs187043211

Positions:

chr1-64841507-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS2

The NM_002227.4(JAK1):c.2498A>G(p.Asn833Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000305 in 1,614,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

JAK1
NM_002227.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2O:1

Conservation

PhyloP100: 1.06

Variant links:

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]

JAK1 links:

JAK1 (HGNC:):

JAK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a domain Protein kinase 1 (size 272) in uniprot entity JAK1_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_002227.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), JAK1. . Gene score misZ 4.6073 (greater than the threshold 3.09). Trascript score misZ 5.8568 (greater than threshold 3.09). GenCC has associacion of gene with autoinflammation, immune dysregulation, and eosinophilia.

BP4

Computational evidence support a benign effect (MetaRNN=0.014337182).

BP6

Variant 1-64841507-T-C is Benign according to our data. Variant chr1-64841507-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134544.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, not_provided=1}.

BS2

High AC in GnomAd4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK1	NM_002227.4 linkuse as main transcript	c.2498A>G	p.Asn833Ser	missense_variant	18/25	ENST00000342505.5	NP_002218.2	P23458

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5 linkuse as main transcript	c.2498A>G	p.Asn833Ser	missense_variant	18/25	5	NM_002227.4	ENSP00000343204.4		P23458

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.000405

AC:

101

AN:

249586

Hom.:

AF XY:

0.000443

AC XY:

AN XY:

135410

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000353

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000291

AC:

426

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

218

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000267

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000433

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000332

Hom.:

Bravo

AF:

0.000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000480

AC:

ExAC

AF:

0.000347

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

JAK1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 20, 2023

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). -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Uncertain

0.42

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.69

M_CAP

Benign

0.018

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.55

PrimateAI

Benign

0.36

PROVEAN

Benign

0.21

REVEL

Benign

0.12

Sift

Benign

0.74

Sift4G

Benign

0.73

Polyphen

0.0010

Vest4

0.11

MVP

0.50

MPC

0.86

ClinPred

0.0059

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.091

gMVP

0.35

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over