chr1-64855641-G-A

Position:

chr1-64855641-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_002227.4(JAK1):c.1516C>T(p.Arg506Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000625 in 1,614,062 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R506H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00062 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 2 hom. )

Consequence

JAK1
NM_002227.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: 0.792

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 -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), JAK1. . Gene score misZ 4.6073 (greater than the threshold 3.09). Trascript score misZ 5.8568 (greater than threshold 3.09). GenCC has associacion of gene with autoinflammation, immune dysregulation, and eosinophilia.

BP4

Computational evidence support a benign effect (MetaRNN=0.022575617).

BP6

Variant 1-64855641-G-A is Benign according to our data. Variant chr1-64855641-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134541.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, not_provided=1}.

BS2

High AC in GnomAd4 at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK1	NM_002227.4 linkuse as main transcript	c.1516C>T	p.Arg506Cys	missense_variant	11/25	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.1516C>T	p.Arg506Cys	missense_variant	11/25	5	NM_002227.4	ENSP00000343204.4		P23458

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000663

AC:

165

AN:

249038

Hom.:

AF XY:

0.000666

AC XY:

AN XY:

135164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000510

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000625

AC:

913

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000723

AC XY:

526

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00111

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000562

Gnomad4 NFE exome

AF:

0.000719

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000624

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000995

Hom.:

Bravo

AF:

0.000578

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00144

AC:

ExAC

AF:

0.000637

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autoinflammation, immune dysregulation, and eosinophilia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 25, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 09, 2022	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.1% [80/68036] including 1 homozygote; https://gnomad.broadinstitute.org/variant/1-64855641-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID: 134541). This variant amino acid Cysteine (Cys) is present in several species multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.68

M_CAP

Benign

0.015

MetaRNN

Benign

0.023

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.5

REVEL

Benign

0.10

Sift

Benign

0.053

Sift4G

Uncertain

0.051

Polyphen

0.66

Vest4

0.058

MVP

0.48

MPC

1.1

ClinPred

0.050

GERP RS

-0.030

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.64

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