NM_003331.5:c.1087G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003331.5(TYK2):c.1087G>A(p.Gly363Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,613,992 control chromosomes in the GnomAD database, including 4,365 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 295 hom., cov: 33)

Exomes 𝑓: 0.072 ( 4070 hom. )

Consequence

TYK2
NM_003331.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.30

Publications

39 publications found

Variant links:

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

TYK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002353698).

BP6

Variant 19-10364973-C-T is Benign according to our data. Variant chr19-10364973-C-T is described in ClinVar as Benign. ClinVar VariationId is 137864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TYK2	NM_003331.5	MANE Select	c.1087G>A	p.Gly363Ser	missense	Exon 8 of 25	NP_003322.3
TYK2	NM_001385204.1		c.1087G>A	p.Gly363Ser	missense	Exon 8 of 25	NP_001372133.1
TYK2	NM_001385203.1		c.1087G>A	p.Gly363Ser	missense	Exon 8 of 26	NP_001372132.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TYK2	ENST00000525621.6	TSL:1 MANE Select	c.1087G>A	p.Gly363Ser	missense	Exon 8 of 25	ENSP00000431885.1	P29597
TYK2	ENST00000524462.5	TSL:1	c.532G>A	p.Gly178Ser	missense	Exon 4 of 21	ENSP00000433203.1	E9PM19
TYK2	ENST00000531836.7	TSL:4	c.1087G>A	p.Gly363Ser	missense	Exon 8 of 25	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes

AF:

0.0550

AC:

8378

AN:

152256

Hom.:

291

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0157

Gnomad AMI

AF:

0.0789

Gnomad AMR

AF:

0.0463

Gnomad ASJ

AF:

0.0724

Gnomad EAS

AF:

0.0250

Gnomad SAS

AF:

0.0775

Gnomad FIN

AF:

0.0688

Gnomad MID

AF:

0.0764

Gnomad NFE

AF:

0.0782

Gnomad OTH

AF:

0.0550

GnomAD2 exomes

AF:

0.0622

AC:

15602

AN:

250708

AF XY:

0.0647

show subpopulations

Gnomad AFR exome

AF:

0.0154

Gnomad AMR exome

AF:

0.0312

Gnomad ASJ exome

AF:

0.0729

Gnomad EAS exome

AF:

0.0239

Gnomad FIN exome

AF:

0.0670

Gnomad NFE exome

AF:

0.0768

Gnomad OTH exome

AF:

0.0711

GnomAD4 exome

AF:

0.0719

AC:

105111

AN:

1461618

Hom.:

4070

Cov.:

AF XY:

0.0727

AC XY:

52865

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.0146

AC:

488

AN:

33480

American (AMR)

AF:

0.0334

AC:

1493

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0699

AC:

1827

AN:

26134

East Asian (EAS)

AF:

0.0156

AC:

619

AN:

39696

South Asian (SAS)

AF:

0.0813

AC:

7014

AN:

86256

European-Finnish (FIN)

AF:

0.0671

AC:

3570

AN:

53220

Middle Eastern (MID)

AF:

0.0631

AC:

364

AN:

5766

European-Non Finnish (NFE)

AF:

0.0769

AC:

85555

AN:

1111962

Other (OTH)

AF:

0.0692

AC:

4181

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

6306

12612

18917

25223

31529

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3134

6268

9402

12536

15670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0551

AC:

8399

AN:

152374

Hom.:

295

Cov.:

AF XY:

0.0547

AC XY:

4079

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.0159

AC:

663

AN:

41592

American (AMR)

AF:

0.0463

AC:

709

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0724

AC:

251

AN:

3468

East Asian (EAS)

AF:

0.0248

AC:

129

AN:

5192

South Asian (SAS)

AF:

0.0774

AC:

374

AN:

4834

European-Finnish (FIN)

AF:

0.0688

AC:

731

AN:

10628

Middle Eastern (MID)

AF:

0.0753

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0782

AC:

5322

AN:

68034

Other (OTH)

AF:

0.0596

AC:

126

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

413

826

1240

1653

2066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0658

Hom.:

174

Bravo

AF:

0.0516

TwinsUK

AF:

0.0782

AC:

290

ALSPAC

AF:

0.0789

AC:

304

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.0784

AC:

674

ExAC

AF:

0.0636

AC:

7724

Asia WGS

AF:

0.0610

AC:

213

AN:

3478

EpiCase

AF:

0.0771

EpiControl

AF:

0.0738

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 35 (3)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.029

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.051

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.67

PhyloP100

-1.3

PrimateAI

Benign

0.22

PROVEAN

Benign

0.53

REVEL

Benign

0.027

Sift

Benign

0.48

Sift4G

Benign

0.71

Polyphen

0.0020

Vest4

0.047

MPC

0.26

ClinPred

0.0015

GERP RS

-6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.040

gMVP

0.13

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over