Genetic Variant TOLLIP:p.Ala225Thr (chr11-1277191-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_019009.4(TOLLIP):c.673G>A(p.Ala225Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,602,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A225S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

TOLLIP
NM_019009.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.368

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031600446).

BS2

High AC in GnomAdExome4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019009.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOLLIP	NM_019009.4	MANE Select	c.673G>A	p.Ala225Thr	missense	Exon 6 of 6	NP_061882.2
TOLLIP	NM_001318512.2		c.523G>A	p.Ala175Thr	missense	Exon 5 of 5	NP_001305441.1	B3KR28
TOLLIP	NM_001318516.2		c.490G>A	p.Ala164Thr	missense	Exon 5 of 5	NP_001305445.1	F2Z2Y8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOLLIP	ENST00000317204.11	TSL:1 MANE Select	c.673G>A	p.Ala225Thr	missense	Exon 6 of 6	ENSP00000314733.5	Q9H0E2-1
TOLLIP	ENST00000863437.1		c.748G>A	p.Ala250Thr	missense	Exon 7 of 7	ENSP00000533496.1
TOLLIP	ENST00000961564.1		c.733G>A	p.Ala245Thr	missense	Exon 7 of 7	ENSP00000631623.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000285

AC:

AN:

245334

AF XY:

0.0000376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000152

AC:

AN:

1450340

Hom.:

Cov.:

AF XY:

0.0000209

AC XY:

AN XY:

719290

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33286

American (AMR)

AF:

0.0000226

AC:

AN:

44172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25796

East Asian (EAS)

AF:

0.00

AC:

AN:

39360

South Asian (SAS)

AF:

0.0000467

AC:

AN:

85736

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

53016

Middle Eastern (MID)

AF:

0.000874

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00000725

AC:

AN:

1103464

Other (OTH)

AF:

0.0000502

AC:

AN:

59786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

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:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000868

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.2

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.052

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.69

M_CAP

Benign

0.013

MetaRNN

Benign

0.032

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.37

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.31

REVEL

Benign

0.040

Sift

Benign

0.63

Sift4G

Benign

0.61

Polyphen

0.0020

Vest4

0.013

MutPred

0.12

Gain of phosphorylation at A225 (P = 0.0522)

MVP

0.36

MPC

0.43

ClinPred

0.022

GERP RS

-0.017

Varity_R

0.017

gMVP

0.16

Mutation Taster

=94/6

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over