11-1277074-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_019009.4(TOLLIP):c.790A>G(p.Ile264Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,614,038 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (81 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (78 hom.)
• Consequence: TOLLIP NM_019009.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.87

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004539937).
• BP6: Variant 11-1277074-T-C is Benign according to our data. Variant chr11-1277074-T-C is described in ClinVar as [Benign]. Clinvar id is 719474.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOLLIP	NM_019009.4	c.790A>G	p.Ile264Val	missense_variant	6/6	ENST00000317204.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOLLIP	ENST00000317204.11	c.790A>G	p.Ile264Val	missense_variant	6/6	1	NM_019009.4	P1

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2482 AN: 152210 Hom.: 81 Cov.: 33

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00411 AC: 1032 AN: 251208 Hom.: 32 AF XY: 0.00293 AC XY: 398 AN XY: 135824

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00177 AC: 2592 AN: 1461710 Hom.: 78 Cov.: 31 AF XY: 0.00152 AC XY: 1103 AN XY: 727156

Gnomad4 AFR exome AF: 0.0620

Gnomad4 AMR exome AF: 0.00306

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.0163 AC: 2489 AN: 152328 Hom.: 81 Cov.: 33 AF XY: 0.0151 AC XY: 1126 AN XY: 74490

Gnomad4 AFR AF: 0.0569

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00280 Hom.: 9

Bravo AF: 0.0182

ESP6500AA AF: 0.0509 AC: 224

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00502 AC: 610

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 31, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.10	T;.;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D;T;D;T
MetaRNN	Benign	0.0045	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.43	N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.0020	B;.;B;.
Vest4		0.096
MVP		0.31
MPC		0.39
ClinPred		0.0063	T
GERP RS		2.2
Varity_R		0.031
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs111986008; hg19: chr11-1298304;