Genetic Variant TSLP:c.-440C>T (chr5-111071044-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000420978.6(TSLP):c.-440C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 160,814 control chromosomes in the GnomAD database, including 14,022 homozygotes. 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 0.40 ( 13188 hom., cov: 32)

Exomes 𝑓: 0.42 ( 834 hom. )

Consequence

TSLP
ENST00000420978.6 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.728

Publications

76 publications found

Variant links:

Genes affected

TSLP (HGNC:30743): (thymic stromal lymphopoietin) This gene encodes a hemopoietic cytokine proposed to signal through a heterodimeric receptor complex composed of the thymic stromal lymphopoietin receptor and the IL-7R alpha chain. It mainly impacts myeloid cells and induces the release of T cell-attracting chemokines from monocytes and enhances the maturation of CD11c(+) dendritic cells. The protein promotes T helper type 2 (TH2) cell responses that are associated with immunity in various inflammatory diseases, including asthma, allergic inflammation and chronic obstructive pulmonary disease. The protein is therefore considered a potential therapeutic target for the treatment of such diseases. In addition, the shorter (predominant) isoform is an antimicrobial protein, displaying antibacterial and antifungal activity against B. cereus, E. coli, E. faecalis, S. mitis, S. epidermidis, and C. albicans. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2020]

TSLP links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSLP	NR_045089.2 link	n.983C>T		non_coding_transcript_exon_variant	Exon 1 of 5
TSLP	XM_047417847.1 link	c.-129+624C>T		intron_variant	Intron 1 of 4		XP_047273803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSLP	ENST00000420978.6 link	c.-440C>T		5_prime_UTR_variant	Exon 1 of 5	1		ENSP00000399099.2

Frequencies

GnomAD3 genomes

AF:

0.405

AC:

61459

AN:

151920

Hom.:

13187

Cov.:

show subpopulations

Gnomad AFR

AF:

0.272

Gnomad AMI

AF:

0.346

Gnomad AMR

AF:

0.427

Gnomad ASJ

AF:

0.465

Gnomad EAS

AF:

0.333

Gnomad SAS

AF:

0.663

Gnomad FIN

AF:

0.538

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.443

Gnomad OTH

AF:

0.426

GnomAD4 exome

AF:

0.424

AC:

3720

AN:

8776

Hom.:

834

Cov.:

AF XY:

0.423

AC XY:

1931

AN XY:

4560

show subpopulations

African (AFR)

AF:

0.286

AC:

110

AN:

384

American (AMR)

AF:

0.444

AC:

181

AN:

408

Ashkenazi Jewish (ASJ)

AF:

0.429

AC:

168

AN:

392

East Asian (EAS)

AF:

0.297

AC:

140

AN:

472

South Asian (SAS)

AF:

0.685

AC:

115

AN:

168

European-Finnish (FIN)

AF:

0.508

AC:

184

AN:

362

Middle Eastern (MID)

AF:

0.600

AC:

AN:

European-Non Finnish (NFE)

AF:

0.426

AC:

2531

AN:

5938

Other (OTH)

AF:

0.436

AC:

267

AN:

612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

111

222

333

444

555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.404

AC:

61477

AN:

152038

Hom.:

13188

Cov.:

AF XY:

0.412

AC XY:

30656

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.272

AC:

11280

AN:

41458

American (AMR)

AF:

0.427

AC:

6526

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.465

AC:

1616

AN:

3472

East Asian (EAS)

AF:

0.334

AC:

1726

AN:

5174

South Asian (SAS)

AF:

0.664

AC:

3199

AN:

4818

European-Finnish (FIN)

AF:

0.538

AC:

5686

AN:

10572

Middle Eastern (MID)

AF:

0.575

AC:

169

AN:

294

European-Non Finnish (NFE)

AF:

0.443

AC:

30072

AN:

67958

Other (OTH)

AF:

0.422

AC:

888

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1844

3688

5533

7377

9221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

602

1204

1806

2408

3010

<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:

0.418

Hom.:

38353

Bravo

AF:

0.381

Asia WGS

AF:

0.478

AC:

1665

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.46

(source)

DANN

Benign

0.64

PhyloP100

-0.73

Mutation Taster

=300/0

polymorphism (auto)

(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