rs146550489

Positions:

• chr19-4817821-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182919.4(TICAM1):​c.557C>T​(p.Ser186Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000239 in 1,604,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: TICAM1 NM_182919.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.751

Genes affected

TICAM1 (HGNC:18348): (TIR domain containing adaptor molecule 1) This gene encodes an adaptor protein containing a Toll/interleukin-1 receptor (TIR) homology domain, which is an intracellular signaling domain that mediates protein-protein interactions between the Toll-like receptors (TLRs) and signal-transduction components. This protein is involved in native immunity against invading pathogens. It specifically interacts with toll-like receptor 3, but not with other TLRs, and this association mediates dsRNA induction of interferon-beta through activation of nuclear factor kappa-B, during an antiviral immune response. Mutations in this gene are associated with encephalopathy, acute, infection-induced. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01178211).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TICAM1	NM_182919.4	c.557C>T	p.Ser186Leu	missense_variant	2/2	ENST00000248244.6	NP_891549.1
TICAM1	NM_001385678.1	c.515C>T	p.Ser172Leu	missense_variant	3/3		NP_001372607.1
TICAM1	NM_001385679.1	c.422C>T	p.Ser141Leu	missense_variant	2/2		NP_001372608.1
TICAM1	NM_001385680.1	c.-71-15C>T		intron_variant			NP_001372609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICAM1	ENST00000248244.6	c.557C>T	p.Ser186Leu	missense_variant	2/2	1	NM_182919.4	ENSP00000248244.4

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000307 AC: 74 AN: 241128 Hom.: 0 AF XY: 0.000268 AC XY: 35 AN XY: 130816

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.000410

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000667

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.000671

GnomAD4 exome AF: 0.000203 AC: 295 AN: 1452532 Hom.: 0 Cov.: 77 AF XY: 0.000191 AC XY: 138 AN XY: 722002

Gnomad4 AFR exome AF: 0.000659

Gnomad4 AMR exome AF: 0.000474

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.000483

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74444

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000353 Hom.: 1

Bravo AF: 0.000831

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000321 AC: 39

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 4 Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 07, 2022	- -
risk factor, no assertion criteria provided	literature only	OMIM	Dec 01, 2011	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 186 of the TICAM1 protein (p.Ser186Leu). This variant is present in population databases (rs146550489, gnomAD 0.2%). This missense change has been observed in individual(s) with herpes simplex encephalitis (PMID: 22105173). This variant is also known as TRIF. ClinVar contains an entry for this variant (Variation ID: 37266). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects TICAM1 function (PMID: 22105173). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.8
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	D;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D;.
Sift4G	Benign	0.065	T;T
Polyphen		0.0	B;.
Vest4		0.12
MVP		0.76
MPC		0.20
ClinPred		0.012	T
GERP RS		1.1
Varity_R		0.062

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: rs146550489; hg19: chr19-4817833;