Variant chr11-1288625-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_019009.4(TOLLIP):c.518C>T(p.Ala173Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,611,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

TOLLIP
NM_019009.4 missense, splice_region

Scores

Splicing: ADA: 0.9808

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.29

Variant links:

Genes affected

TOLLIP (HGNC:16476): (toll interacting protein) This gene encodes a ubiquitin-binding protein that interacts with several Toll-like receptor (TLR) signaling cascade components. The encoded protein regulates inflammatory signaling and is involved in interleukin-1 receptor trafficking and in the turnover of IL1R-associated kinase. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

TOLLIP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOLLIP	NM_019009.4 linkuse as main transcript	c.518C>T	p.Ala173Val	missense_variant, splice_region_variant	4/6	ENST00000317204.11	NP_061882.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOLLIP	ENST00000317204.11 linkuse as main transcript	c.518C>T	p.Ala173Val	missense_variant, splice_region_variant	4/6	1	NM_019009.4	ENSP00000314733	P1	Q9H0E2-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000109

AC:

AN:

248074

Hom.:

AF XY:

0.0000818

AC XY:

AN XY:

134542

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000708

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000487

AC:

AN:

1458936

Hom.:

Cov.:

AF XY:

0.0000455

AC XY:

AN XY:

725760

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.000454

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000396

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000908

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2024

The c.518C>T (p.A173V) alteration is located in exon 4 (coding exon 4) of the TOLLIP gene. This alteration results from a C to T substitution at nucleotide position 518, causing the alanine (A) at amino acid position 173 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;T;T;.

Eigen

Benign

0.091

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.054

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.0

N;N;N;N;N

REVEL

Benign

0.091

Sift

Benign

0.075

T;T;T;T;T

Sift4G

Benign

0.31

T;T;T;T;.

Polyphen

0.027

B;.;B;.;.

Vest4

0.24

MVP

0.56

MPC

0.46

ClinPred

0.047

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.061

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.77

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over