rs17127063

Variant names:

• chr1-64846659-G-A
• rs17127063
• NM_002227.4:c.1977C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-64846659-G-A
• chr1-64846659-G-C
• chr1-64846659-G-T

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.1977C>T​(p.Arg659Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0321 in 1,613,140 control chromosomes in the GnomAD database, including 1,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (304 hom., cov: 32)
  • Exomes 𝑓: 0.030 (793 hom.)
• Consequence: JAK1 NM_002227.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.48
• 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: STRONG, MODERATE Submitted by: 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=-0.79).
• BP6: Variant 1-64846659-G-A is Benign according to our data. Variant chr1-64846659-G-A is described in ClinVar as Benign. ClinVar VariationId is 1169784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	NM_002227.4	MANE Select	c.1977C>T	p.Arg659Arg	synonymous	Exon 14 of 25	NP_002218.2
	JAK1	NM_001320923.2		c.1977C>T	p.Arg659Arg	synonymous	Exon 15 of 26	NP_001307852.1
	JAK1	NM_001321852.2		c.1977C>T	p.Arg659Arg	synonymous	Exon 14 of 25	NP_001308781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	ENST00000342505.5	TSL:5 MANE Select	c.1977C>T	p.Arg659Arg	synonymous	Exon 14 of 25	ENSP00000343204.4
	JAK1	ENST00000671929.2		c.1977C>T	p.Arg659Arg	synonymous	Exon 15 of 26	ENSP00000500485.1
	JAK1	ENST00000671954.2		c.1977C>T	p.Arg659Arg	synonymous	Exon 15 of 26	ENSP00000500841.1

Frequencies

GnomAD3 genomes AF: 0.0517 AC: 7857 AN: 152052 Hom.: 303 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0450

GnomAD2 exomes AF: 0.0309 AC: 7710 AN: 249160 AF XY: 0.0296

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0650

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.0280

Gnomad NFE exome AF: 0.0284

Gnomad OTH exome AF: 0.0312

GnomAD4 exome AF: 0.0300 AC: 43855 AN: 1460970 Hom.: 793 Cov.: 30 AF XY: 0.0296 AC XY: 21484 AN XY: 726806

African (AFR) AF: 0.114 AC: 3807 AN: 33450

American (AMR) AF: 0.0208 AC: 928 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 1704 AN: 26118

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.0184 AC: 1583 AN: 86218

European-Finnish (FIN) AF: 0.0265 AC: 1417 AN: 53380

Middle Eastern (MID) AF: 0.0316 AC: 182 AN: 5762

European-Non Finnish (NFE) AF: 0.0290 AC: 32242 AN: 1111280

Other (OTH) AF: 0.0328 AC: 1981 AN: 60364

GnomAD4 genome AF: 0.0517 AC: 7865 AN: 152170 Hom.: 304 Cov.: 32 AF XY: 0.0505 AC XY: 3760 AN XY: 74394

African (AFR) AF: 0.113 AC: 4672 AN: 41476

American (AMR) AF: 0.0267 AC: 409 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 225 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4826

European-Finnish (FIN) AF: 0.0302 AC: 320 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0297 AC: 2020 AN: 68020

Other (OTH) AF: 0.0445 AC: 94 AN: 2110

Alfa AF: 0.0383 Hom.: 426

Bravo AF: 0.0544

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0308

EpiControl AF: 0.0305

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

JAK1-related disorder Benign:1

Jul 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.1
DANN	Benign	0.55
PhyloP100		-4.5
PromoterAI		0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs17127063; hg19: chr1-65312342; COSMIC: COSV61088458;