rs7536540

Positions:

• chr1-65058899-C-G
• chr1-65058899-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK1	NM_001321852.2	c.-78+8705G>C		intron_variant			NP_001308781.1
JAK1	NM_001321853.2	c.-162+7729G>C		intron_variant			NP_001308782.1
JAK1	NM_001321854.2	c.-78+7729G>C		intron_variant			NP_001308783.1
JAK1	XM_047419676.1	c.-78+8705G>C		intron_variant			XP_047275632.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000671954.2	c.-181+8705G>C		intron_variant				ENSP00000500841.1
JAK1	ENST00000672434.2	c.-162+7729G>C		intron_variant				ENSP00000499900.1
JAK1	ENST00000672751.2	c.-78+8705G>C		intron_variant				ENSP00000500745.2

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

Gnomad4 AFR AF: 0.493

Gnomad4 AMR AF: 0.589

Gnomad4 ASJ AF: 0.755

Gnomad4 EAS AF: 0.578

Gnomad4 SAS AF: 0.748

Gnomad4 FIN AF: 0.785

Gnomad4 NFE AF: 0.736

Gnomad4 OTH AF: 0.677

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 v4.3

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

Splicing

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

Publications

LitVar

Other links and lift over

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