Genetic Variant TSLP:c.216+237G>A (chr5-111073169-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_033035.5(TSLP):c.216+237G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 906,686 control chromosomes in the GnomAD database, including 115 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 0.018 ( 88 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 27 hom. )

Consequence

TSLP
NM_033035.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.962

Publications

3 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=-0.75).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033035.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TSLP	NM_033035.5	MANE Select	c.216+237G>A	intron	N/A	NP_149024.1
TSLP	NR_045089.2		n.1638+237G>A	intron	N/A
TSLP	NM_138551.5		c.-414G>A	upstream_gene	N/A	NP_612561.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TSLP	ENST00000344895.4	TSL:1 MANE Select	c.216+237G>A	intron	N/A	ENSP00000339804.3
TSLP	ENST00000420978.6	TSL:1	c.216+237G>A	intron	N/A	ENSP00000399099.2
TSLP	ENST00000379706.4	TSL:1	c.-414G>A	upstream_gene	N/A	ENSP00000427827.1

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2811

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00477

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:

0.000118

Gnomad OTH

AF:

0.0124

GnomAD4 exome

AF:

0.00166

AC:

1252

AN:

754332

Hom.:

AF XY:

0.00132

AC XY:

503

AN XY:

380290

show subpopulations

African (AFR)

AF:

0.0597

AC:

1057

AN:

17702

American (AMR)

AF:

0.00281

AC:

AN:

16732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15272

East Asian (EAS)

AF:

0.00

AC:

AN:

31188

South Asian (SAS)

AF:

0.000208

AC:

AN:

47968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29596

Middle Eastern (MID)

AF:

0.00119

AC:

AN:

2516

European-Non Finnish (NFE)

AF:

0.0000179

AC:

AN:

557716

Other (OTH)

AF:

0.00351

AC:

125

AN:

35642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.0185

AC:

2818

AN:

152354

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1307

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.0652

AC:

2710

AN:

41582

American (AMR)

AF:

0.00477

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68034

Other (OTH)

AF:

0.0123

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

142

283

425

566

708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0144

Hom.:

Bravo

AF:

0.0202

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

0.96

PromoterAI

0.11

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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