11-1295674-C-A

Variant names:

• chr11-1295674-C-A
• rs769026579
• NM_019009.4:c.154G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001318514.2(TOLLIP):​c.-54G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TOLLIP NM_001318514.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3336426).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318514.2. 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.154G>T	p.Val52Leu	missense	Exon 2 of 6	NP_061882.2
	TOLLIP	NM_001318514.2		c.-54G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001305443.1	Q9H0E2-2
	TOLLIP	NM_001318516.2		c.154G>T	p.Val52Leu	missense	Exon 2 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.154G>T	p.Val52Leu	missense	Exon 2 of 6	ENSP00000314733.5	Q9H0E2-1
	TOLLIP	ENST00000527886.5	TSL:2	c.-54G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000434035.1	Q9H0E2-2
	TOLLIP	ENST00000863437.1		c.154G>T	p.Val52Leu	missense	Exon 2 of 7	ENSP00000533496.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448786 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719010

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33278

American (AMR) AF: 0.00 AC: 0 AN: 44138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25662

East Asian (EAS) AF: 0.00 AC: 0 AN: 39384

South Asian (SAS) AF: 0.00 AC: 0 AN: 85418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103362

Other (OTH) AF: 0.00 AC: 0 AN: 59768

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.0063	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.18
Sift	Benign	0.086	T
Sift4G	Benign	0.24	T
Polyphen		0.027	B
Vest4		0.42
MutPred		0.63		Loss of MoRF binding (P = 0.0998)
MVP		0.52
MPC		0.44
ClinPred		0.55	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.11
gMVP		0.43
Mutation Taster		=74/26	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: rs769026579; hg19: chr11-1316904;