rs310216

Variant names:

• chr1-64850992-G-A
• rs310216
• NM_002227.4:c.1649-82C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-64850992-G-A
• chr1-64850992-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002227.4(JAK1):​c.1649-82C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 908,368 control chromosomes in the GnomAD database, including 38,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10831 hom., cov: 32)
  • Exomes 𝑓: 0.26 (28105 hom.)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.197

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-64850992-G-A is Benign according to our data. Variant chr1-64850992-G-A is described in ClinVar as [Benign]. Clinvar id is 2628196.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4	c.1649-82C>T		intron_variant	Intron 11 of 24	ENST00000342505.5	NP_002218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5	c.1649-82C>T		intron_variant	Intron 11 of 24	5	NM_002227.4	ENSP00000343204.4

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52800 AN: 151932 Hom.: 10793 Cov.: 32

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.264 AC: 199858 AN: 756318 Hom.: 28105 AF XY: 0.261 AC XY: 103646 AN XY: 396802

Gnomad4 AFR exome AF: 0.584

Gnomad4 AMR exome AF: 0.345

Gnomad4 ASJ exome AF: 0.354

Gnomad4 EAS exome AF: 0.293

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.276

Gnomad4 NFE exome AF: 0.241

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome AF: 0.348 AC: 52897 AN: 152050 Hom.: 10831 Cov.: 32 AF XY: 0.347 AC XY: 25759 AN XY: 74316

Gnomad4 AFR AF: 0.578

Gnomad4 AMR AF: 0.306

Gnomad4 ASJ AF: 0.357

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.338

Alfa AF: 0.274 Hom.: 6090

Bravo AF: 0.362

Asia WGS AF: 0.309 AC: 1074 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 45% of patients studied by a panel of primary immunodeficiencies. Number of patients: 43. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.66

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: rs310216; hg19: chr1-65316675;