rs17000728

Positions:

• chr19-10380511-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000524462.5(TYK2):​c.-92G>A variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00525 in 152,360 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. 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 ENST00000524462.5 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.0002899
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -0.00300

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 19-10380511-C-T is Benign according to our data. Variant chr19-10380511-C-T is described in ClinVar as [Benign]. Clinvar id is 440730.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00525 (800/152360) while in subpopulation EAS AF= 0.0315 (163/5176). AF 95% confidence interval is 0.0275. There are 14 homozygotes in gnomad4. There are 540 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYK2	NM_003331.5	c.-317G>A		5_prime_UTR_variant	1/25	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.-317G>A		5_prime_UTR_variant	1/25	1	NM_003331.5	ENSP00000431885	P1

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 802 AN: 152242 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0318

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 230 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 146

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.00525 AC: 800 AN: 152360 Hom.: 14 Cov.: 32 AF XY: 0.00725 AC XY: 540 AN XY: 74490

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0315

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0442

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00339 Hom.: 0

Bravo AF: 0.00206

Asia WGS AF: 0.0290 AC: 101 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Virus-induced diabetes Uncertain:1

Uncertain significance, no assertion criteria provided

reference population

Division of Host Defense, Kyushu University

-

- -

Immunodeficiency 35 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.024

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

Publications

LitVar

Other links and lift over

dbSNP: rs17000728; hg19: chr19-10491187;