Genetic Variant NM_002227.4:c.3096G>A (chr1-64837976-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002227.4(JAK1):c.3096G>A(p.Lys1032Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0901 in 1,613,920 control chromosomes in the GnomAD database, including 7,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.076 ( 566 hom., cov: 32)

Exomes 𝑓: 0.092 ( 7028 hom. )

Consequence

JAK1
NM_002227.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.53

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

autoinflammation, immune dysregulation, and eosinophilia
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

JAK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.22).

BP6

Variant 1-64837976-C-T is Benign according to our data. Variant chr1-64837976-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.53 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4 link	c.3096G>A	p.Lys1032Lys	synonymous_variant	Exon 22 of 25	ENST00000342505.5	NP_002218.2	P23458

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5 link	c.3096G>A	p.Lys1032Lys	synonymous_variant	Exon 22 of 25	5	NM_002227.4	ENSP00000343204.4		P23458

Frequencies

GnomAD3 genomes

AF:

0.0763

AC:

11601

AN:

152116

Hom.:

566

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0341

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.0796

Gnomad ASJ

AF:

0.0934

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0128

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.0871

GnomAD2 exomes

AF:

0.0766

AC:

19123

AN:

249512

AF XY:

0.0757

show subpopulations

Gnomad AFR exome

AF:

0.0347

Gnomad AMR exome

AF:

0.0536

Gnomad ASJ exome

AF:

0.0967

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.0950

GnomAD4 exome

AF:

0.0916

AC:

133865

AN:

1461686

Hom.:

7028

Cov.:

AF XY:

0.0900

AC XY:

65441

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.0323

AC:

1081

AN:

33480

American (AMR)

AF:

0.0572

AC:

2557

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0940

AC:

2457

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0146

AC:

1256

AN:

86256

European-Finnish (FIN)

AF:

0.112

AC:

5987

AN:

53420

Middle Eastern (MID)

AF:

0.0829

AC:

478

AN:

5768

European-Non Finnish (NFE)

AF:

0.104

AC:

115101

AN:

1111822

Other (OTH)

AF:

0.0819

AC:

4945

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

5761

11521

17282

23042

28803

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3960

7920

11880

15840

19800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0761

AC:

11592

AN:

152234

Hom.:

566

Cov.:

AF XY:

0.0759

AC XY:

5650

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0340

AC:

1414

AN:

41536

American (AMR)

AF:

0.0794

AC:

1213

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0934

AC:

324

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.0122

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.113

AC:

1201

AN:

10598

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7072

AN:

68020

Other (OTH)

AF:

0.0862

AC:

182

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

548

1095

1643

2190

2738

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0934

Hom.:

612

Bravo

AF:

0.0742

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.109

EpiControl

AF:

0.105

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Benign

7.8

(source)

DANN

Benign

0.87

PhyloP100

1.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over