rs61735631

Variant names:

• chr1-64855641-G-A
• rs61735631
• NM_002227.4:c.1516C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. 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. 15/22 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:2 O:1
• Conservation: PhyloP100: 0.792
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• autoinflammation, immune dysregulation, and eosinophilia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• 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 VariationId is 134541.
• BS2: High AC in GnomAd4 at 95 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	NM_002227.4	MANE Select	c.1516C>T	p.Arg506Cys	missense	Exon 11 of 25	NP_002218.2	P23458
	JAK1	NM_001320923.2		c.1516C>T	p.Arg506Cys	missense	Exon 12 of 26	NP_001307852.1	P23458
	JAK1	NM_001321852.2		c.1516C>T	p.Arg506Cys	missense	Exon 11 of 25	NP_001308781.1	P23458

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	ENST00000342505.5	TSL:5 MANE Select	c.1516C>T	p.Arg506Cys	missense	Exon 11 of 25	ENSP00000343204.4	P23458
	JAK1	ENST00000671929.2		c.1516C>T	p.Arg506Cys	missense	Exon 12 of 26	ENSP00000500485.1	P23458
	JAK1	ENST00000671954.2		c.1516C>T	p.Arg506Cys	missense	Exon 12 of 26	ENSP00000500841.1	P23458

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

GnomAD2 exomes AF: 0.000663 AC: 165 AN: 249038 AF XY: 0.000666

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000719 AC: 799 AN: 1111960

Other (OTH) AF: 0.000613 AC: 37 AN: 60394

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152242 Hom.: 1 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74432

African (AFR) AF: 0.0000482 AC: 2 AN: 41520

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00101 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Autoinflammation, immune dysregulation, and eosinophilia (2)
-	-	2	not provided (2)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.79
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
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

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