rs310229

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002227.4(JAK1):c.1459-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,606,088 control chromosomes in the GnomAD database, including 88,904 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13244 hom., cov: 32)

Exomes 𝑓: 0.32 ( 75660 hom. )

Consequence

JAK1
NM_002227.4 splice_region, intron

Scores

Splicing: ADA: 0.00003188

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.269

Publications

16 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 1-64855705-G-A is Benign according to our data. Variant chr1-64855705-G-A is described in ClinVar as [Benign]. Clinvar id is 1169785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4 link	c.1459-7C>T		splice_region_variant, intron_variant	Intron 10 of 24	ENST00000342505.5	NP_002218.2	P23458

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5 link	c.1459-7C>T		splice_region_variant, intron_variant	Intron 10 of 24	5	NM_002227.4	ENSP00000343204.4		P23458

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

60592

AN:

151784

Hom.:

13198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.584

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.392

Gnomad EAS

AF:

0.309

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.328

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.306

Gnomad OTH

AF:

0.377

GnomAD2 exomes

AF:

0.359

AC:

87990

AN:

245004

AF XY:

0.347

show subpopulations

Gnomad AFR exome

AF:

0.586

Gnomad AMR exome

AF:

0.520

Gnomad ASJ exome

AF:

0.391

Gnomad EAS exome

AF:

0.330

Gnomad FIN exome

AF:

0.329

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.345

GnomAD4 exome

AF:

0.316

AC:

459018

AN:

1454186

Hom.:

75660

Cov.:

AF XY:

0.314

AC XY:

227173

AN XY:

722518

show subpopulations

African (AFR)

AF:

0.595

AC:

19830

AN:

33350

American (AMR)

AF:

0.510

AC:

22611

AN:

44348

Ashkenazi Jewish (ASJ)

AF:

0.389

AC:

10110

AN:

26016

East Asian (EAS)

AF:

0.304

AC:

12008

AN:

39548

South Asian (SAS)

AF:

0.297

AC:

25525

AN:

85902

European-Finnish (FIN)

AF:

0.321

AC:

17113

AN:

53320

Middle Eastern (MID)

AF:

0.302

AC:

1737

AN:

5754

European-Non Finnish (NFE)

AF:

0.299

AC:

330552

AN:

1105910

Other (OTH)

AF:

0.325

AC:

19532

AN:

60038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

13266

26533

39799

53066

66332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11044

22088

33132

44176

55220

<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:

0.400

AC:

60699

AN:

151902

Hom.:

13244

Cov.:

AF XY:

0.399

AC XY:

29660

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.585

AC:

24180

AN:

41368

American (AMR)

AF:

0.447

AC:

6814

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.392

AC:

1362

AN:

3472

East Asian (EAS)

AF:

0.308

AC:

1593

AN:

5172

South Asian (SAS)

AF:

0.292

AC:

1405

AN:

4810

European-Finnish (FIN)

AF:

0.328

AC:

3459

AN:

10544

Middle Eastern (MID)

AF:

0.259

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.306

AC:

20790

AN:

67972

Other (OTH)

AF:

0.383

AC:

809

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1761

3522

5282

7043

8804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<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:

0.362

Hom.:

4696

Bravo

AF:

0.418

Asia WGS

AF:

0.339

AC:

1179

AN:

3478

EpiCase

AF:

0.312

EpiControl

AF:

0.303

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

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 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

3.4

(source)

DANN

Benign

0.32

PhyloP100

0.27

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0

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