chr1-64835418-C-T

Position:

chr1-64835418-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_002227.4(JAK1):c.3347G>A(p.Cys1116Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000081 in 1,604,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. C1116C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

JAK1
NM_002227.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21

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 -4 ACMG points.

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=0.34959453).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK1	NM_002227.4 linkuse as main transcript	c.3347G>A	p.Cys1116Tyr	missense_variant	24/25	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.3347G>A	p.Cys1116Tyr	missense_variant	24/25	5	NM_002227.4	ENSP00000343204.4		P23458

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

244548

Hom.:

AF XY:

0.00000752

AC XY:

AN XY:

132952

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000171

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000757

AC:

AN:

1452676

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

723216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.0000999

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000384

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

Asia WGS

AF:

0.00173

AC:

AN:

3478

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1116 of the JAK1 protein (p.Cys1116Tyr). This variant is present in population databases (rs368093469, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with JAK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1469780). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt JAK1 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.69

Eigen

Benign

-0.015

Eigen_PC

Benign

-0.041

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.068

MetaRNN

Benign

0.35

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.80

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.28

Sift

Benign

0.30

Sift4G

Benign

0.19

Polyphen

0.93

Vest4

0.40

MutPred

0.43

Loss of catalytic residue at P1115 (P = 0.0121);

MVP

0.71

MPC

2.6

ClinPred

0.31

GERP RS

5.2

Varity_R

0.22

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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