dbSNP rs7531799: JAK1:c.-78+23920A>G (chr1-64942413-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_002227.4(JAK1):c.-78+23920A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 152,112 control chromosomes in the GnomAD database, including 5,827 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 5827 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

JAK1
NM_002227.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.31

Publications

1 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:

ENSG00000233877 (HGNC:):

ENSG00000233877 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.513 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
JAK1	NM_002227.4	MANE Select	c.-78+23920A>G	intron	N/A	NP_002218.2
JAK1	NM_001320923.2		c.-78+14521A>G	intron	N/A	NP_001307852.1
JAK1	NM_001321852.2		c.-77-56072A>G	intron	N/A	NP_001308781.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
JAK1	ENST00000342505.5	TSL:5 MANE Select	c.-78+23920A>G	intron	N/A	ENSP00000343204.4
JAK1	ENST00000671929.2		c.-78+14521A>G	intron	N/A	ENSP00000500485.1
JAK1	ENST00000671954.2		c.-77-56072A>G	intron	N/A	ENSP00000500841.1

Frequencies

GnomAD3 genomes

AF:

0.243

AC:

36888

AN:

151994

Hom.:

5817

Cov.:

show subpopulations

Gnomad AFR

AF:

0.414

Gnomad AMI

AF:

0.182

Gnomad AMR

AF:

0.182

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.530

Gnomad SAS

AF:

0.191

Gnomad FIN

AF:

0.291

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.206

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.243

AC:

36931

AN:

152112

Hom.:

5827

Cov.:

AF XY:

0.250

AC XY:

18551

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.414

AC:

17166

AN:

41448

American (AMR)

AF:

0.182

AC:

2784

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

413

AN:

3470

East Asian (EAS)

AF:

0.530

AC:

2740

AN:

5170

South Asian (SAS)

AF:

0.191

AC:

923

AN:

4830

European-Finnish (FIN)

AF:

0.291

AC:

3078

AN:

10578

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.135

AC:

9210

AN:

68004

Other (OTH)

AF:

0.203

AC:

430

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1298

2596

3895

5193

6491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<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:

0.157

Hom.:

2234

Bravo

AF:

0.246

Asia WGS

AF:

0.360

AC:

1248

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

1.3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over