Genetic Variant TOLLIP:p.Val223Leu (chr11-1277197-C-A) – 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.667G>T(p.Val223Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000625 in 1,600,220 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. V223M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TOLLIP
NM_019009.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.199

Publications

2 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=0.06267974).

BS2

High AC in GnomAdExome4 at 9 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.667G>T	p.Val223Leu	missense	Exon 6 of 6	NP_061882.2
TOLLIP	NM_001318512.2		c.517G>T	p.Val173Leu	missense	Exon 5 of 5	NP_001305441.1	B3KR28
TOLLIP	NM_001318516.2		c.484G>T	p.Val162Leu	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.667G>T	p.Val223Leu	missense	Exon 6 of 6	ENSP00000314733.5	Q9H0E2-1
TOLLIP	ENST00000863437.1		c.742G>T	p.Val248Leu	missense	Exon 7 of 7	ENSP00000533496.1
TOLLIP	ENST00000961564.1		c.727G>T	p.Val243Leu	missense	Exon 7 of 7	ENSP00000631623.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000450

AC:

AN:

244192

AF XY:

0.0000453

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000550

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.00000622

AC:

AN:

1447984

Hom.:

Cov.:

AF XY:

0.00000836

AC XY:

AN XY:

717768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33224

American (AMR)

AF:

0.00

AC:

AN:

44034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25718

East Asian (EAS)

AF:

0.000178

AC:

AN:

39308

South Asian (SAS)

AF:

0.00

AC:

AN:

85502

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101906

Other (OTH)

AF:

0.0000168

AC:

AN:

59654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2090

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.1

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.10

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.77

M_CAP

Benign

0.018

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

0.20

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.58

REVEL

Benign

0.016

Sift

Benign

0.36

Sift4G

Benign

0.77

Polyphen

0.0050

Vest4

0.026

MutPred

0.22

Gain of glycosylation at P220 (P = 0.092)

MVP

0.49

MPC

0.44

ClinPred

0.024

GERP RS

1.7

Varity_R

0.023

gMVP

0.17

Mutation Taster

=96/4

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