1-64834565-T-A

Variant names:

• chr1-64834565-T-A
• rs769371012
• NM_002227.4:c.3462A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002227.4(JAK1):​c.3462A>T​(p.Lys1154Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000417 in 1,439,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: JAK1 NM_002227.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autoinflammation, immune dysregulation, and eosinophilia

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15119097).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4	c.3462A>T	p.Lys1154Asn	missense_variant	Exon 25 of 25	ENST00000342505.5	NP_002218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5	c.3462A>T	p.Lys1154Asn	missense_variant	Exon 25 of 25	5	NM_002227.4	ENSP00000343204.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248470 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000417 AC: 6 AN: 1439906 Hom.: 0 Cov.: 27 AF XY: 0.00000418 AC XY: 3 AN XY: 717686

African (AFR) AF: 0.00 AC: 0 AN: 32970

American (AMR) AF: 0.000135 AC: 6 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39514

South Asian (SAS) AF: 0.00 AC: 0 AN: 85370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092842

Other (OTH) AF: 0.00 AC: 0 AN: 59666

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1154 of the JAK1 protein (p.Lys1154Asn). This variant is present in population databases (rs769371012, 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: 1367133). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.087
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.96	L
PhyloP100		3.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.24
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.079	T
Polyphen		0.30	B
Vest4		0.31
MutPred		0.34		Loss of ubiquitination at K1154 (P = 0.0183);
MVP		0.75
MPC		1.4
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.21
gMVP		0.38
Mutation Taster		=89/11	polymorphism

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: rs769371012; hg19: chr1-65300248;