chr11-1288704-C-T

Variant names:

• chr11-1288704-C-T
• rs749743149
• NM_019009.4:c.439G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_019009.4(TOLLIP):​c.439G>A​(p.Val147Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,460,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V147E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TOLLIP NM_019009.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37104234).
• BS2: High AC in GnomAdExome4 at 23 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOLLIP	NM_019009.4	MANE Select	c.439G>A	p.Val147Met	missense	Exon 4 of 6	NP_061882.2
	TOLLIP	NM_001318512.2		c.289G>A	p.Val97Met	missense	Exon 3 of 5	NP_001305441.1	B3KR28
	TOLLIP	NM_001318516.2		c.256G>A	p.Val86Met	missense	Exon 3 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.439G>A	p.Val147Met	missense	Exon 4 of 6	ENSP00000314733.5	Q9H0E2-1
	TOLLIP	ENST00000863437.1		c.439G>A	p.Val147Met	missense	Exon 4 of 7	ENSP00000533496.1
	TOLLIP	ENST00000961564.1		c.499G>A	p.Val167Met	missense	Exon 5 of 7	ENSP00000631623.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 249952 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460610 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726624

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44704

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111864

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.29
Sift	Benign	0.055	T
Sift4G	Uncertain	0.044	D
Polyphen		0.98	D
Vest4		0.30
MutPred		0.17		Gain of disorder (P = 0.0745)
MVP		0.89
MPC		0.79
ClinPred		0.83	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.50
Mutation Taster		=75/25	polymorphism

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: rs749743149; hg19: chr11-1309934;