1-64845531-G-C

Variant names:

Variant summary

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

The NM_002227.4(JAK1):c.2097C>G(p.Ala699Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 1,613,920 control chromosomes in the GnomAD database, including 4,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 337 hom., cov: 33)

Exomes 𝑓: 0.065 ( 3728 hom. )

Consequence

JAK1
NM_002227.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.899

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 1-64845531-G-C is Benign according to our data. Variant chr1-64845531-G-C is described in ClinVar as [Benign]. Clinvar id is 1166648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.899 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4 link	c.2097C>G	p.Ala699Ala	synonymous_variant	Exon 15 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.2097C>G	p.Ala699Ala	synonymous_variant	Exon 15 of 25	5	NM_002227.4	ENSP00000343204.4		P23458

Frequencies

GnomAD3 genomes

AF:

0.0531

AC:

8078

AN:

152132

Hom.:

334

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0117

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.0352

Gnomad EAS

AF:

0.0127

Gnomad SAS

AF:

0.0616

Gnomad FIN

AF:

0.0402

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0640

Gnomad OTH

AF:

0.0478

GnomAD3 exomes

AF:

0.0666

AC:

16633

AN:

249572

Hom.:

913

AF XY:

0.0650

AC XY:

8797

AN XY:

135402

show subpopulations

Gnomad AFR exome

AF:

0.00943

Gnomad AMR exome

AF:

0.168

Gnomad ASJ exome

AF:

0.0349

Gnomad EAS exome

AF:

0.0114

Gnomad SAS exome

AF:

0.0639

Gnomad FIN exome

AF:

0.0425

Gnomad NFE exome

AF:

0.0612

Gnomad OTH exome

AF:

0.0541

GnomAD4 exome

AF:

0.0649

AC:

94847

AN:

1461670

Hom.:

3728

Cov.:

AF XY:

0.0648

AC XY:

47146

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.0106

Gnomad4 AMR exome

AF:

0.162

Gnomad4 ASJ exome

AF:

0.0358

Gnomad4 EAS exome

AF:

0.00804

Gnomad4 SAS exome

AF:

0.0659

Gnomad4 FIN exome

AF:

0.0455

Gnomad4 NFE exome

AF:

0.0668

Gnomad4 OTH exome

AF:

0.0559

GnomAD4 genome

AF:

0.0531

AC:

8085

AN:

152250

Hom.:

337

Cov.:

AF XY:

0.0542

AC XY:

4035

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0117

Gnomad4 AMR

AF:

0.142

Gnomad4 ASJ

AF:

0.0352

Gnomad4 EAS

AF:

0.0125

Gnomad4 SAS

AF:

0.0625

Gnomad4 FIN

AF:

0.0402

Gnomad4 NFE

AF:

0.0640

Gnomad4 OTH

AF:

0.0469

Alfa

AF:

0.0465

Hom.:

Bravo

AF:

0.0574

Asia WGS

AF:

0.0300

AC:

105

AN:

3478

EpiCase

AF:

0.0636

EpiControl

AF:

0.0602

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 27% of patients studied by a panel of primary immunodeficiencies. Number of patients: 26. Only high quality variants are reported. -

JAK1-related disorder

Benign:1

Jun 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

-0.50

CADD

Benign

9.7

DANN

Benign

0.63

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