19-10350700-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003331.5(TYK2):c.*134A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00626 in 1,097,606 control chromosomes in the GnomAD database, including 286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (193 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (93 hom.)
• Consequence: TYK2 NM_003331.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.416

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-10350700-T-C is Benign according to our data. Variant chr19-10350700-T-C is described in ClinVar as [Benign]. Clinvar id is 327933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.094 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYK2	NM_003331.5	c.*134A>G		3_prime_UTR_variant	25/25	ENST00000525621.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYK2	ENST00000525621.6	c.*134A>G		3_prime_UTR_variant	25/25	1	NM_003331.5	P1

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4235 AN: 152132 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0962

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.00276 AC: 2610 AN: 945356 Hom.: 93 Cov.: 12 AF XY: 0.00239 AC XY: 1151 AN XY: 480676

Gnomad4 AFR exome AF: 0.0962

Gnomad4 AMR exome AF: 0.00639

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000107

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000879

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.0280 AC: 4257 AN: 152250 Hom.: 193 Cov.: 32 AF XY: 0.0265 AC XY: 1974 AN XY: 74444

Gnomad4 AFR AF: 0.0965

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00587 Hom.: 26

Bravo AF: 0.0315

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2019

- -

Immunodeficiency 35 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.7
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs12720334; hg19: chr19-10461376;