rs17000730

Variant names:

• chr19-10380572-T-C
• rs17000730
• NM_003331.5:c.-378A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003331.5(TYK2):​c.-378A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00527 in 152,056 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TYK2 NM_003331.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -1.43
• Publications: 4 publications found

Genes affected

TYK2 (HGNC:12440): (tyrosine kinase 2) This gene encodes a member of the tyrosine kinase and, more specifically, the Janus kinases (JAKs) protein families. This protein associates with the cytoplasmic domain of type I and type II cytokine receptors and promulgate cytokine signals by phosphorylating receptor subunits. It is also a component of both the type I and type III interferon signaling pathways. As such, it may play a role in anti-viral immunity. A mutation in this gene has been associated with Immunodeficiency 35. [provided by RefSeq, Sep 2020]

TYK2 Gene-Disease associations (from GenCC):

• immunodeficiency 35

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-10380572-T-C is Benign according to our data. Variant chr19-10380572-T-C is described in ClinVar as Benign. ClinVar VariationId is 327969.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00527 (801/152056) while in subpopulation EAS AF = 0.0318 (164/5164). AF 95% confidence interval is 0.0278. There are 14 homozygotes in GnomAd4. There are 541 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003331.5. 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
	TYK2	NM_003331.5	MANE Select	c.-378A>G		5_prime_UTR	Exon 1 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.-378A>G		5_prime_UTR	Exon 1 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.-378A>G		5_prime_UTR	Exon 1 of 26	NP_001372132.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.-378A>G		5_prime_UTR	Exon 1 of 25	ENSP00000431885.1	P29597
	TYK2	ENST00000531836.7	TSL:4	c.-288A>G		5_prime_UTR	Exon 1 of 25	ENSP00000436175.2	P29597
	TYK2	ENST00000955974.1		c.-158A>G		5_prime_UTR	Exon 1 of 25	ENSP00000626033.1

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 803 AN: 151972 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00481

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 274 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 184

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 142

South Asian (SAS) AF: 0.00 AC: 0 AN: 32

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 88

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00527 AC: 801 AN: 152056 Hom.: 14 Cov.: 32 AF XY: 0.00728 AC XY: 541 AN XY: 74280

African (AFR) AF: 0.000362 AC: 15 AN: 41488

American (AMR) AF: 0.00164 AC: 25 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.0318 AC: 164 AN: 5164

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4818

European-Finnish (FIN) AF: 0.0445 AC: 469 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 68016

Other (OTH) AF: 0.00477 AC: 10 AN: 2098

Alfa AF: 0.00357 Hom.: 2

Bravo AF: 0.00204

Asia WGS AF: 0.0290 AC: 101 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 35 (1)
-	1	-	Virus-induced diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.37
DANN	Benign	0.65
PhyloP100		-1.4
PromoterAI		0.072	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs17000730; hg19: chr19-10491248;