NM_002227.4:c.2097C>G

Variant names:

• chr1-64845531-G-C
• rs3737139
• NM_002227.4:c.2097C>G

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.2097C>G​(p.Ala699Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 1,613,920 control chromosomes in the GnomAD database, including 4,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (337 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3728 hom.)
• Consequence: JAK1 NM_002227.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.899
• Publications: 21 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=-0.5).
• BP6: Variant 1-64845531-G-C is Benign according to our data. Variant chr1-64845531-G-C is described in ClinVar as Benign. ClinVar VariationId is 1166648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.899 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.137 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.2097C>G	p.Ala699Ala	synonymous	Exon 15 of 25	NP_002218.2
	JAK1	NM_001320923.2		c.2097C>G	p.Ala699Ala	synonymous	Exon 16 of 26	NP_001307852.1
	JAK1	NM_001321852.2		c.2097C>G	p.Ala699Ala	synonymous	Exon 15 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.2097C>G	p.Ala699Ala	synonymous	Exon 15 of 25	ENSP00000343204.4
	JAK1	ENST00000671929.2		c.2097C>G	p.Ala699Ala	synonymous	Exon 16 of 26	ENSP00000500485.1
	JAK1	ENST00000671954.2		c.2097C>G	p.Ala699Ala	synonymous	Exon 16 of 26	ENSP00000500841.1

Frequencies

GnomAD3 genomes AF: 0.0531 AC: 8078 AN: 152132 Hom.: 334 Cov.: 33

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.0616

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0640

Gnomad OTH AF: 0.0478

GnomAD2 exomes AF: 0.0666 AC: 16633 AN: 249572 AF XY: 0.0650

Gnomad AFR exome AF: 0.00943

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.0349

Gnomad EAS exome AF: 0.0114

Gnomad FIN exome AF: 0.0425

Gnomad NFE exome AF: 0.0612

Gnomad OTH exome AF: 0.0541

GnomAD4 exome AF: 0.0649 AC: 94847 AN: 1461670 Hom.: 3728 Cov.: 33 AF XY: 0.0648 AC XY: 47146 AN XY: 727150

African (AFR) AF: 0.0106 AC: 354 AN: 33478

American (AMR) AF: 0.162 AC: 7246 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0358 AC: 935 AN: 26134

East Asian (EAS) AF: 0.00804 AC: 319 AN: 39700

South Asian (SAS) AF: 0.0659 AC: 5684 AN: 86254

European-Finnish (FIN) AF: 0.0455 AC: 2433 AN: 53416

Middle Eastern (MID) AF: 0.0366 AC: 211 AN: 5768

European-Non Finnish (NFE) AF: 0.0668 AC: 74288 AN: 1111816

Other (OTH) AF: 0.0559 AC: 3377 AN: 60382

GnomAD4 genome AF: 0.0531 AC: 8085 AN: 152250 Hom.: 337 Cov.: 33 AF XY: 0.0542 AC XY: 4035 AN XY: 74448

African (AFR) AF: 0.0117 AC: 484 AN: 41542

American (AMR) AF: 0.142 AC: 2169 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3470

East Asian (EAS) AF: 0.0125 AC: 65 AN: 5182

South Asian (SAS) AF: 0.0625 AC: 301 AN: 4816

European-Finnish (FIN) AF: 0.0402 AC: 427 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0640 AC: 4354 AN: 68008

Other (OTH) AF: 0.0469 AC: 99 AN: 2112

Alfa AF: 0.0465 Hom.: 77

Bravo AF: 0.0574

Asia WGS AF: 0.0300 AC: 105 AN: 3478

EpiCase AF: 0.0636

EpiControl AF: 0.0602

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 27% of patients studied by a panel of primary immunodeficiencies. Number of patients: 26. Only high quality variants are reported.

JAK1-related disorder Benign:1

Jun 27, 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	-0.50
CADD	Benign	9.7
DANN	Benign	0.63
PhyloP100		0.90
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3737139; hg19: chr1-65311214; COSMIC: COSV61087128; COSMIC: COSV61087128;