11-1277077-C-A

Variant names:

• chr11-1277077-C-A
• rs146354036
• NM_019009.4:c.787G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_019009.4(TOLLIP):​c.787G>T​(p.Ala263Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. A263T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TOLLIP NM_019009.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.18
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.787G>T	p.Ala263Ser	missense	Exon 6 of 6	NP_061882.2
	TOLLIP	NM_001318512.2		c.637G>T	p.Ala213Ser	missense	Exon 5 of 5	NP_001305441.1	B3KR28
	TOLLIP	NM_001318516.2		c.604G>T	p.Ala202Ser	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.787G>T	p.Ala263Ser	missense	Exon 6 of 6	ENSP00000314733.5	Q9H0E2-1
	TOLLIP	ENST00000863437.1		c.862G>T	p.Ala288Ser	missense	Exon 7 of 7	ENSP00000533496.1
	TOLLIP	ENST00000961564.1		c.847G>T	p.Ala283Ser	missense	Exon 7 of 7	ENSP00000631623.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.26
Sift	Uncertain	0.013	D
Sift4G	Benign	0.081	T
Polyphen		1.0	D
Vest4		0.70
MutPred		0.47		Gain of disorder (P = 0.0278)
MVP		0.56
MPC		1.2
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.14
gMVP		0.50
Mutation Taster		=35/65	disease causing

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: rs146354036; hg19: chr11-1298307;