rs578481

Variant names:

• chr1-65063072-T-C
• rs578481
• NM_001321852.2:c.-78+4532A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-65063072-T-C
• chr1-65063072-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001321852.2(JAK1):​c.-78+4532A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 152,232 control chromosomes in the GnomAD database, including 1,784 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1784 hom., cov: 32)
• Consequence: JAK1 NM_001321852.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.40
• Publications: 4 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: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_001321852.2	c.-78+4532A>G		intron_variant	Intron 1 of 24		NP_001308781.1
JAK1	NM_001321853.2	c.-162+3556A>G		intron_variant	Intron 2 of 26		NP_001308782.1
JAK1	NM_001321854.2	c.-78+3556A>G		intron_variant	Intron 2 of 25		NP_001308783.1
JAK1	XM_047419676.1	c.-78+4532A>G		intron_variant	Intron 1 of 24		XP_047275632.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000671954.2	c.-181+4532A>G		intron_variant	Intron 1 of 25			ENSP00000500841.1
JAK1	ENST00000672434.2	c.-162+3556A>G		intron_variant	Intron 2 of 26			ENSP00000499900.1
JAK1	ENST00000672751.2	c.-78+4532A>G		intron_variant	Intron 1 of 24			ENSP00000500745.2

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21284 AN: 152114 Hom.: 1784 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.0879

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0918

Gnomad OTH AF: 0.136

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.140 AC: 21320 AN: 152232 Hom.: 1784 Cov.: 32 AF XY: 0.142 AC XY: 10570 AN XY: 74448

African (AFR) AF: 0.215 AC: 8914 AN: 41510

American (AMR) AF: 0.131 AC: 2005 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0879 AC: 305 AN: 3470

East Asian (EAS) AF: 0.300 AC: 1555 AN: 5176

South Asian (SAS) AF: 0.157 AC: 755 AN: 4822

European-Finnish (FIN) AF: 0.105 AC: 1112 AN: 10614

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0918 AC: 6248 AN: 68024

Other (OTH) AF: 0.139 AC: 294 AN: 2110

Alfa AF: 0.117 Hom.: 1327

Bravo AF: 0.148

Asia WGS AF: 0.219 AC: 758 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.037
DANN	Benign	0.20
PhyloP100		-4.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs578481; hg19: chr1-65528755;