1-65058899-C-G

Variant names:

• chr1-65058899-C-G
• rs7536540
• NM_001321852.2:c.-78+8705G>C

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+8705G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 151,952 control chromosomes in the GnomAD database, including 33,498 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 0.65 (33498 hom., cov: 30)
• Consequence: JAK1 NM_001321852.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.688
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321852.2. 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_001321852.2		c.-78+8705G>C		intron	N/A	NP_001308781.1	P23458
	JAK1	NM_001321853.2		c.-162+7729G>C		intron	N/A	NP_001308782.1	P23458
	JAK1	NM_001321854.2		c.-78+7729G>C		intron	N/A	NP_001308783.1	P23458

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	ENST00000671954.2		c.-181+8705G>C		intron	N/A	ENSP00000500841.1	P23458
	JAK1	ENST00000672434.2		c.-162+7729G>C		intron	N/A	ENSP00000499900.1	P23458
	JAK1	ENST00000672751.2		c.-78+8705G>C		intron	N/A	ENSP00000500745.2	P23458

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99269 AN: 151834 Hom.: 33512 Cov.: 30

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.825

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.755

Gnomad EAS AF: 0.578

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.683

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

GnomAD4 genome AF: 0.653 AC: 99263 AN: 151952 Hom.: 33498 Cov.: 30 AF XY: 0.656 AC XY: 48752 AN XY: 74268

African (AFR) AF: 0.493 AC: 20402 AN: 41404

American (AMR) AF: 0.589 AC: 8992 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.755 AC: 2620 AN: 3470

East Asian (EAS) AF: 0.578 AC: 2982 AN: 5160

South Asian (SAS) AF: 0.748 AC: 3603 AN: 4818

European-Finnish (FIN) AF: 0.785 AC: 8283 AN: 10558

Middle Eastern (MID) AF: 0.685 AC: 200 AN: 292

European-Non Finnish (NFE) AF: 0.736 AC: 50000 AN: 67966

Other (OTH) AF: 0.677 AC: 1429 AN: 2110

Alfa AF: 0.632 Hom.: 2271

Bravo AF: 0.630

Asia WGS AF: 0.611 AC: 2128 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.32
DANN	Benign	0.36
PhyloP100		-0.69

Splicing

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

Other links and lift over

dbSNP: rs7536540; hg19: chr1-65524582; COSMIC: COSV63010257;