19-4816328-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_182919.4(TICAM1):c.2050G>A(p.Ala684Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000422 in 1,422,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: TICAM1 NM_182919.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.34

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TICAM1	NM_182919.4	c.2050G>A	p.Ala684Thr	missense_variant	2/2	ENST00000248244.6
TICAM1	NM_001385678.1	c.2008G>A	p.Ala670Thr	missense_variant	3/3
TICAM1	NM_001385679.1	c.1915G>A	p.Ala639Thr	missense_variant	2/2
TICAM1	NM_001385680.1	c.1408G>A	p.Ala470Thr	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TICAM1	ENST00000248244.6	c.2050G>A	p.Ala684Thr	missense_variant	2/2	1	NM_182919.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000138 AC: 3 AN: 217584 Hom.: 0 AF XY: 0.0000171 AC XY: 2 AN XY: 116874

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000300

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000422 AC: 6 AN: 1422836 Hom.: 0 Cov.: 36 AF XY: 0.00000425 AC XY: 3 AN XY: 705070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000548

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Jul 06, 2023

PM2_SUP, BP4 -

Herpes simplex encephalitis, susceptibility to, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2021

This sequence change replaces alanine with threonine at codon 684 of the TICAM1 protein (p.Ala684Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs376421303, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with TICAM1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.72	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.65	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.69
MVP		0.67
MPC		0.81
ClinPred		0.81	D
GERP RS		4.7
Varity_R		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs376421303; hg19: chr19-4816340; COSMIC: COSV50231757;