Variant rs17127063 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002227.4(JAK1):c.1977C>T(p.Arg659Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0321 in 1,613,140 control chromosomes in the GnomAD database, including 1,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 304 hom., cov: 32)

Exomes 𝑓: 0.030 ( 793 hom. )

Consequence

JAK1
NM_002227.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.48

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:

JAK1 (HGNC:):

JAK1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 1-64846659-G-A is Benign according to our data. Variant chr1-64846659-G-A is described in ClinVar as [Benign]. Clinvar id is 1169784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.48 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK1	NM_002227.4 linkuse as main transcript	c.1977C>T	p.Arg659Arg	synonymous_variant	14/25	ENST00000342505.5	NP_002218.2	P23458

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5 linkuse as main transcript	c.1977C>T	p.Arg659Arg	synonymous_variant	14/25	5	NM_002227.4	ENSP00000343204.4		P23458

Frequencies

GnomAD3 genomes

AF:

0.0517

AC:

7857

AN:

152052

Hom.:

303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0268

Gnomad ASJ

AF:

0.0649

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0161

Gnomad FIN

AF:

0.0302

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0297

Gnomad OTH

AF:

0.0450

GnomAD3 exomes

AF:

0.0309

AC:

7710

AN:

249160

Hom.:

195

AF XY:

0.0296

AC XY:

3995

AN XY:

135182

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.0197

Gnomad ASJ exome

AF:

0.0650

Gnomad EAS exome

AF:

0.000334

Gnomad SAS exome

AF:

0.0181

Gnomad FIN exome

AF:

0.0280

Gnomad NFE exome

AF:

0.0284

Gnomad OTH exome

AF:

0.0312

GnomAD4 exome

AF:

0.0300

AC:

43855

AN:

1460970

Hom.:

793

Cov.:

AF XY:

0.0296

AC XY:

21484

AN XY:

726806

show subpopulations

Gnomad4 AFR exome

AF:

0.114

Gnomad4 AMR exome

AF:

0.0208

Gnomad4 ASJ exome

AF:

0.0652

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0184

Gnomad4 FIN exome

AF:

0.0265

Gnomad4 NFE exome

AF:

0.0290

Gnomad4 OTH exome

AF:

0.0328

GnomAD4 genome

AF:

0.0517

AC:

7865

AN:

152170

Hom.:

304

Cov.:

AF XY:

0.0505

AC XY:

3760

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.113

Gnomad4 AMR

AF:

0.0267

Gnomad4 ASJ

AF:

0.0649

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0160

Gnomad4 FIN

AF:

0.0302

Gnomad4 NFE

AF:

0.0297

Gnomad4 OTH

AF:

0.0445

Alfa

AF:

0.0372

Hom.:

290

Bravo

AF:

0.0544

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0308

EpiControl

AF:

0.0305

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

JAK1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.1

DANN

Benign

0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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