rs61735631

chr1-64855641-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 0.792

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, JAK1
• 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: {not_provided=1, Uncertain_significance=2, Likely_benign=1}.
• BS2: High AC in GnomAd at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK1	NM_002227.4	c.1516C>T	p.Arg506Cys	missense_variant	11/25	ENST00000342505.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK1	ENST00000342505.5	c.1516C>T	p.Arg506Cys	missense_variant	11/25	5	NM_002227.4	A1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152124 Hom.: 1 Cov.: 32

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.: 0 AF XY: 0.000666 AC XY: 90 AN XY: 135164

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.: 2 Cov.: 31 AF XY: 0.000723 AC XY: 526 AN XY: 727202

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: 95 AN: 152242 Hom.: 1 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74432

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.: 2

Bravo AF: 0.000578

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00144 AC: 12

ExAC AF: 0.000637 AC: 77

EpiCase AF: 0.00136

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

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

Invitae

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	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.053	T
Sift4G	Uncertain	0.051	T
Polyphen		0.66	P
Vest4		0.058
MVP		0.48
MPC		1.1
ClinPred		0.050	T
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

Other links and lift over

dbSNP: rs61735631; hg19: chr1-65321324; COSMIC: COSV61089402; COSMIC: COSV61089402;