rs2289276

Variant names:

• chr5-111071809-C-T
• rs2289276
• NM_033035.5:c.-82C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033035.5(TSLP):​c.-82C>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 0.3 in 1,520,870 control chromosomes in the GnomAD database, including 70,795 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 0.28 (6236 hom., cov: 33)
  • Exomes 𝑓: 0.30 (64559 hom.)
• Consequence: TSLP NM_033035.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.125
• Publications: 81 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSLP	NM_033035.5	c.-82C>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000344895.4	NP_149024.1
TSLP	NR_045089.2	n.1457-116C>T		intron_variant	Intron 1 of 4
TSLP	XM_047417846.1	c.4+63C>T		intron_variant	Intron 1 of 4		XP_047273802.1
TSLP	XM_047417847.1	c.-128-116C>T		intron_variant	Intron 1 of 4		XP_047273803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSLP	ENST00000344895.4	c.-82C>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_033035.5	ENSP00000339804.3
TSLP	ENST00000420978.6	c.35-116C>T		intron_variant	Intron 1 of 4	1		ENSP00000399099.2

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41914 AN: 152080 Hom.: 6230 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.301

GnomAD4 exome AF: 0.303 AC: 414714 AN: 1368672 Hom.: 64559 Cov.: 23 AF XY: 0.306 AC XY: 207261 AN XY: 676560

African (AFR) AF: 0.166 AC: 5166 AN: 31122

American (AMR) AF: 0.407 AC: 15864 AN: 38976

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 8122 AN: 22118

East Asian (EAS) AF: 0.265 AC: 10319 AN: 38966

South Asian (SAS) AF: 0.396 AC: 29891 AN: 75392

European-Finnish (FIN) AF: 0.381 AC: 19404 AN: 50988

Middle Eastern (MID) AF: 0.405 AC: 2188 AN: 5396

European-Non Finnish (NFE) AF: 0.292 AC: 306362 AN: 1048986

Other (OTH) AF: 0.307 AC: 17398 AN: 56728

GnomAD4 genome AF: 0.275 AC: 41930 AN: 152198 Hom.: 6236 Cov.: 33 AF XY: 0.283 AC XY: 21045 AN XY: 74412

African (AFR) AF: 0.173 AC: 7190 AN: 41550

American (AMR) AF: 0.338 AC: 5171 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1255 AN: 3470

East Asian (EAS) AF: 0.268 AC: 1388 AN: 5176

South Asian (SAS) AF: 0.385 AC: 1854 AN: 4818

European-Finnish (FIN) AF: 0.396 AC: 4195 AN: 10590

Middle Eastern (MID) AF: 0.445 AC: 130 AN: 292

European-Non Finnish (NFE) AF: 0.293 AC: 19906 AN: 67998

Other (OTH) AF: 0.297 AC: 626 AN: 2110

Alfa AF: 0.294 Hom.: 11509

Bravo AF: 0.267

Asia WGS AF: 0.306 AC: 1065 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.6
DANN	Benign	0.84
PhyloP100		0.13
PromoterAI		0.023	Neutral
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2289276; hg19: chr5-110407507; COSMIC: COSV61291363; COSMIC: COSV61291363;