rs45598436

Variant names:

• chr1-64869379-A-G
• rs45598436
• NM_002227.4:c.579T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002227.4(JAK1):​c.579T>C​(p.Ala193Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0912 in 1,613,434 control chromosomes in the GnomAD database, including 7,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (577 hom., cov: 32)
  • Exomes 𝑓: 0.093 (7175 hom.)
• Consequence: JAK1 NM_002227.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.07
• Publications: 13 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: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-64869379-A-G is Benign according to our data. Variant chr1-64869379-A-G is described in ClinVar as Benign. ClinVar VariationId is 1168339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	NM_002227.4	MANE Select	c.579T>C	p.Ala193Ala	synonymous	Exon 6 of 25	NP_002218.2	P23458
	JAK1	NM_001320923.2		c.579T>C	p.Ala193Ala	synonymous	Exon 7 of 26	NP_001307852.1	P23458
	JAK1	NM_001321852.2		c.579T>C	p.Ala193Ala	synonymous	Exon 6 of 25	NP_001308781.1	P23458

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	ENST00000342505.5	TSL:5 MANE Select	c.579T>C	p.Ala193Ala	synonymous	Exon 6 of 25	ENSP00000343204.4	P23458
	JAK1	ENST00000671929.2		c.579T>C	p.Ala193Ala	synonymous	Exon 7 of 26	ENSP00000500485.1	P23458
	JAK1	ENST00000671954.2		c.579T>C	p.Ala193Ala	synonymous	Exon 7 of 26	ENSP00000500841.1	P23458

Frequencies

GnomAD3 genomes AF: 0.0776 AC: 11808 AN: 152086 Hom.: 577 Cov.: 32

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0793

Gnomad ASJ AF: 0.0948

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0860

GnomAD2 exomes AF: 0.0775 AC: 19326 AN: 249384 AF XY: 0.0764

Gnomad AFR exome AF: 0.0391

Gnomad AMR exome AF: 0.0543

Gnomad ASJ exome AF: 0.0975

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0958

GnomAD4 exome AF: 0.0926 AC: 135296 AN: 1461230 Hom.: 7175 Cov.: 31 AF XY: 0.0910 AC XY: 66161 AN XY: 726944

African (AFR) AF: 0.0371 AC: 1241 AN: 33468

American (AMR) AF: 0.0577 AC: 2579 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0946 AC: 2472 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0146 AC: 1259 AN: 86254

European-Finnish (FIN) AF: 0.112 AC: 5993 AN: 53402

Middle Eastern (MID) AF: 0.0839 AC: 484 AN: 5766

European-Non Finnish (NFE) AF: 0.105 AC: 116252 AN: 1111412

Other (OTH) AF: 0.0830 AC: 5013 AN: 60382

GnomAD4 genome AF: 0.0775 AC: 11803 AN: 152204 Hom.: 577 Cov.: 32 AF XY: 0.0769 AC XY: 5722 AN XY: 74394

African (AFR) AF: 0.0378 AC: 1572 AN: 41552

American (AMR) AF: 0.0791 AC: 1210 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0948 AC: 329 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0127 AC: 61 AN: 4812

European-Finnish (FIN) AF: 0.113 AC: 1199 AN: 10590

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7126 AN: 67988

Other (OTH) AF: 0.0851 AC: 180 AN: 2116

Alfa AF: 0.0911 Hom.: 536

Bravo AF: 0.0758

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.106

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.68
DANN	Benign	0.57
PhyloP100		-1.1
Mutation Taster		=99/1	polymorphism (auto)

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: rs45598436; hg19: chr1-65335062; COSMIC: COSV61087391; COSMIC: COSV61087391;