rs12129819

chr1-64837976-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_002227.4(JAK1):c.3096G>A(p.Lys1032=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0901 in 1,613,920 control chromosomes in the GnomAD database, including 7,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.076 (566 hom., cov: 32)
  • Exomes 𝑓: 0.092 (7028 hom.)
• Consequence: JAK1 NM_002227.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.53

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 1-64837976-C-T is Benign according to our data. Variant chr1-64837976-C-T is described in ClinVar as [Benign]. Clinvar id is 1168338.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK1	NM_002227.4	c.3096G>A	p.Lys1032=	synonymous_variant	22/25	ENST00000342505.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK1	ENST00000342505.5	c.3096G>A	p.Lys1032=	synonymous_variant	22/25	5	NM_002227.4	A1

Frequencies

GnomAD3 genomes AF: 0.0763 AC: 11601 AN: 152116 Hom.: 566 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0796

Gnomad ASJ AF: 0.0934

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0871

GnomAD3 exomes AF: 0.0766 AC: 19123 AN: 249512 Hom.: 999 AF XY: 0.0757 AC XY: 10252 AN XY: 135378

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.0536

Gnomad ASJ exome AF: 0.0967

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0149

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.0950

GnomAD4 exome AF: 0.0916 AC: 133865 AN: 1461686 Hom.: 7028 Cov.: 32 AF XY: 0.0900 AC XY: 65441 AN XY: 727146

Gnomad4 AFR exome AF: 0.0323

Gnomad4 AMR exome AF: 0.0572

Gnomad4 ASJ exome AF: 0.0940

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0146

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.0819

GnomAD4 genome AF: 0.0761 AC: 11592 AN: 152234 Hom.: 566 Cov.: 32 AF XY: 0.0759 AC XY: 5650 AN XY: 74446

Gnomad4 AFR AF: 0.0340

Gnomad4 AMR AF: 0.0794

Gnomad4 ASJ AF: 0.0934

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.0862

Alfa AF: 0.0931 Hom.: 559

Bravo AF: 0.0742

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.109

EpiControl AF: 0.105

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
Cadd	Benign	7.8
Dann	Benign	0.87

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: rs12129819; hg19: chr1-65303659; COSMIC: COSV53805030; COSMIC: COSV53805030;