rs111986008

Variant names:

• chr11-1277074-T-C
• rs111986008
• NM_019009.4:c.790A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 13/20 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.87
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -20 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 VariationId is 719474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOLLIP	NM_019009.4	MANE Select	c.790A>G	p.Ile264Val	missense	Exon 6 of 6	NP_061882.2
	TOLLIP	NM_001318512.2		c.640A>G	p.Ile214Val	missense	Exon 5 of 5	NP_001305441.1	B3KR28
	TOLLIP	NM_001318516.2		c.607A>G	p.Ile203Val	missense	Exon 5 of 5	NP_001305445.1	F2Z2Y8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOLLIP	ENST00000317204.11	TSL:1 MANE Select	c.790A>G	p.Ile264Val	missense	Exon 6 of 6	ENSP00000314733.5	Q9H0E2-1
	TOLLIP	ENST00000863437.1		c.865A>G	p.Ile289Val	missense	Exon 7 of 7	ENSP00000533496.1
	TOLLIP	ENST00000961564.1		c.850A>G	p.Ile284Val	missense	Exon 7 of 7	ENSP00000631623.1

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

GnomAD2 exomes AF: 0.00411 AC: 1032 AN: 251208 AF XY: 0.00293

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 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

African (AFR) AF: 0.0620 AC: 2077 AN: 33480

American (AMR) AF: 0.00306 AC: 137 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53304

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1111960

Other (OTH) AF: 0.00351 AC: 212 AN: 60394

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

African (AFR) AF: 0.0569 AC: 2366 AN: 41574

American (AMR) AF: 0.00562 AC: 86 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68028

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00598 Hom.: 35

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.057
Sift	Benign	0.31	T
Sift4G	Benign	0.48	T
Polyphen		0.0020	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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs111986008; hg19: chr11-1298304;