rs35237903

chr1-64873439-G-Achr1-64873439-G-Cchr1-64873439-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002227.4(JAK1):c.414C>T(p.Tyr138=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,614,122 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (16 hom.)
• Consequence: JAK1 NM_002227.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.982

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-64873439-G-A is Benign according to our data. Variant chr1-64873439-G-A is described in ClinVar as [Benign]. Clinvar id is 1164556.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-64873439-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.982 with no splicing effect.
• BS2: High AC in GnomAd at 148 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK1	NM_002227.4	c.414C>T	p.Tyr138=	synonymous_variant	5/25	ENST00000342505.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK1	ENST00000342505.5	c.414C>T	p.Tyr138=	synonymous_variant	5/25	5	NM_002227.4	A1

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00184 AC: 458 AN: 249388 Hom.: 7 AF XY: 0.00235 AC XY: 318 AN XY: 135286

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00863

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00154 AC: 2255 AN: 1461870 Hom.: 16 Cov.: 31 AF XY: 0.00185 AC XY: 1342 AN XY: 727236

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00880

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74448

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.000771

EpiCase AF: 0.00142

EpiControl AF: 0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.93
Dann	Benign	0.41

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: rs35237903; hg19: chr1-65339122;