dbSNP rs2256298: JAK1:c.991-27C>T (chr1-64864999-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002227.4(JAK1):c.991-27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,571,840 control chromosomes in the GnomAD database, including 61,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.35 ( 10916 hom., cov: 32)

Exomes 𝑓: 0.26 ( 50120 hom. )

Consequence

JAK1
NM_002227.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.181

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-64864999-G-A is Benign according to our data. Variant chr1-64864999-G-A is described in ClinVar as [Benign]. Clinvar id is 2628145.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4 link	c.991-27C>T		intron_variant	Intron 7 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.991-27C>T		intron_variant	Intron 7 of 24	5	NM_002227.4	ENSP00000343204.4		P23458

Frequencies

GnomAD3 genomes

AF:

0.351

AC:

53296

AN:

151904

Hom.:

10874

Cov.:

show subpopulations

Gnomad AFR

AF:

0.570

Gnomad AMI

AF:

0.228

Gnomad AMR

AF:

0.402

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.307

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.239

Gnomad MID

AF:

0.232

Gnomad NFE

AF:

0.241

Gnomad OTH

AF:

0.327

GnomAD3 exomes

AF:

0.303

AC:

72948

AN:

240654

Hom.:

12284

AF XY:

0.290

AC XY:

38000

AN XY:

130834

show subpopulations

Gnomad AFR exome

AF:

0.574

Gnomad AMR exome

AF:

0.467

Gnomad ASJ exome

AF:

0.311

Gnomad EAS exome

AF:

0.333

Gnomad SAS exome

AF:

0.240

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.240

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

AF:

0.257

AC:

364462

AN:

1419818

Hom.:

50120

Cov.:

AF XY:

0.255

AC XY:

180475

AN XY:

707950

show subpopulations

Gnomad4 AFR exome

AF:

0.587

Gnomad4 AMR exome

AF:

0.460

Gnomad4 ASJ exome

AF:

0.308

Gnomad4 EAS exome

AF:

0.303

Gnomad4 SAS exome

AF:

0.235

Gnomad4 FIN exome

AF:

0.237

Gnomad4 NFE exome

AF:

0.238

Gnomad4 OTH exome

AF:

0.269

GnomAD4 genome

AF:

0.351

AC:

53400

AN:

152022

Hom.:

10916

Cov.:

AF XY:

0.351

AC XY:

26056

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.571

Gnomad4 AMR

AF:

0.402

Gnomad4 ASJ

AF:

0.310

Gnomad4 EAS

AF:

0.306

Gnomad4 SAS

AF:

0.227

Gnomad4 FIN

AF:

0.239

Gnomad4 NFE

AF:

0.241

Gnomad4 OTH

AF:

0.334

Alfa

AF:

0.269

Hom.:

8096

Bravo

AF:

0.375

Asia WGS

AF:

0.308

AC:

1073

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 57. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.2

DANN

Benign

0.61

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over