Genetic Variant NM_003331.5:c.-469T>A (chr19-10380663-A-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_003331.5(TYK2):c.-469T>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 85,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 25)

Exomes 𝑓: 0.011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TYK2
NM_003331.5 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.69

Publications

3 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: Orphanet, Labcorp Genetics (formerly Invitae)

TYK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00239 (204/85332) while in subpopulation AFR AF = 0.00525 (88/16760). AF 95% confidence interval is 0.00436. There are 0 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5 link	c.-469T>A		upstream_gene_variant		ENST00000525621.6	NP_003322.3	P29597A0A024R7E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6 link	c.-469T>A		upstream_gene_variant		1	NM_003331.5	ENSP00000431885.1		P29597

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

203

AN:

85344

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00520

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000887

Gnomad ASJ

AF:

0.000470

Gnomad EAS

AF:

0.000306

Gnomad SAS

AF:

0.00154

Gnomad FIN

AF:

0.00452

Gnomad MID

AF:

0.0235

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.00494

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0114

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.0185

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00239

AC:

204

AN:

85332

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

105

AN XY:

41304

show subpopulations

African (AFR)

AF:

0.00525

AC:

AN:

16760

American (AMR)

AF:

0.000885

AC:

AN:

10168

Ashkenazi Jewish (ASJ)

AF:

0.000470

AC:

AN:

2128

East Asian (EAS)

AF:

0.000307

AC:

AN:

3256

South Asian (SAS)

AF:

0.00116

AC:

AN:

2586

European-Finnish (FIN)

AF:

0.00452

AC:

AN:

5086

Middle Eastern (MID)

AF:

0.0256

AC:

AN:

156

European-Non Finnish (NFE)

AF:

0.00157

AC:

AN:

43376

Other (OTH)

AF:

0.00575

AC:

AN:

1218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0242

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.18

(source)

DANN

Benign

0.66

PhyloP100

-1.7

PromoterAI

-0.017

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over