Genetic Variant TSLP:p.Thr134Ala (chr5-111075994-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033035.5(TSLP):c.400A>G(p.Thr134Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TSLP
NM_033035.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.128

Publications

0 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:

ENSG00000253613 (HGNC:):

ENSG00000253613 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05722308).

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	HGVSp	Effect	Exon Rank	Protein	UniProt
TSLP	NM_033035.5	MANE Select	c.400A>G	p.Thr134Ala	missense	Exon 4 of 4	NP_149024.1	Q969D9-1
TSLP	NM_138551.5		c.112A>G	p.Thr38Ala	missense	Exon 2 of 2	NP_612561.2	Q969D9-2
TSLP	NR_045089.2		n.1822A>G		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSLP	ENST00000344895.4	TSL:1 MANE Select	c.400A>G	p.Thr134Ala	missense	Exon 4 of 4	ENSP00000339804.3	Q969D9-1
TSLP	ENST00000420978.6	TSL:1	c.400A>G	p.Thr134Ala	missense	Exon 5 of 5	ENSP00000399099.2	A0A0C4DG43
TSLP	ENST00000379706.4	TSL:1	c.112A>G	p.Thr38Ala	missense	Exon 2 of 2	ENSP00000427827.1	Q969D9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.34

M_CAP

Benign

0.0033

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.13

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.3

REVEL

Benign

0.056

Sift

Pathogenic

0.0

Sift4G

Benign

0.32

Polyphen

0.58

Vest4

0.035

MutPred

0.17

Gain of helix (P = 0.0425)

MVP

0.014

MPC

0.24

ClinPred

0.13

GERP RS

-0.31

Varity_R

0.12

gMVP

0.11

Mutation Taster

=92/8

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over